Cell mechanism discovery could lead to ‘fundamental’ change in leukaemia treatment

Researchers have identified a new cell mechanism that could lead to a fundamental change in the diagnosis and treatment of leukaemia.

A team in the University of Kent’s pharmacy school conducted a study that discovered that leukaemia cells release a protein, known as galctin-9, that prevents a patient’s own immune system from killing cancerous blood cells.

Acute Myeloid Leukaemia (AML) — a type of blood cancer that affects over 250,000 people every year worldwide — progresses rapidly because its cells are capable of avoiding the patient’s immune surveillance. It does this by inactivating the body’s immune cells, cytotoxic T lymphocytes and natural killer (NK) cells.

Existing treatment strategies consist of aggressive chemotherapy and stem cell transplantation, which often do not result in effective remission of the disease. This is because of a lack of understanding of the molecular mechanisms that allow malignant cells to escape attack by the body’s immune cells.

Now the researchers at the Medway School of Pharmacy, led by Dr Vadim Sumbayev, Dr Bernhard Gibbs and Professor Yuri Ushkaryov, have found that leukaemia cells — but not healthy blood cells — express a receptor called latrophilin 1 (LPHN1). Stimulation of this receptor causes these cancer cells to release galectin-9, which then prevents the patient’s immune system from fighting the cancer cells.

The discovery of this cell mechanism paves the way for new ‘biomarkers’ for AML diagnosis, as well as potential targets for AML immune therapy, say the researchers.

‘Targeting this pathway will crucially enhance patients own immune defences, helping them to eliminate leukaemia cells’, said Dr Sumbayev. He added that the discovery has the potential to also be beneficial in the treatment of other cancers.

Study uncovers potential ‘silver bullet’ for preventing and treating colon cancer

In preclinical experiments, researchers at VCU Massey Cancer Center have uncovered a new way in which colon cancer develops, as well as a potential “silver bullet” for preventing and treating it. The findings may extend to ovarian, breast, lung, prostate and potentially other cancers that depend on the same mechanism for growth.

Led by Massey’s Deputy Director Steven Grossman, M.D., Ph.D., a team of scientists targeted the gene CtBP with a drug known as HIPP (2-hydroxy-imino phenylpyruvic acid) and were able to reduce the development of pre-cancerous polyps by half and return a normal lifespan to mice born with a predisposition to intestinal polyps. In humans, this condition is known as familial adenomatous polyposis, a devastating inherited disease that causes pre-cancerous polyps to grow in the intestine at a young age, often leading to the removal of portions of the colon to prevent cancer.

“This work opens up a whole new avenue for anti-cancer therapeutic development, as it shows that CtBP drives the actions of what are known as cancer stem cells, which are keys to cancer metastasis and resistance to chemotherapy,” says Grossman, who is also the Dianne Nunnally Hoppes Endowed Chair in Cancer Research and co-leader of the Developmental Therapeutics research program at Massey as well as professor and chair of the Division of Hematology, Oncology and Palliative Care in the Department of Internal Medicine at the VCU School of Medicine.

In contrast to other cancer-promoting genes, CtBP is not mutated in colon cancer; instead, it is overexpressed to the point where the cancer depends on it for growth. CtBP works to reprogram cells by repressing the expression of genes that typically prevent cancer through a form of cell suicide known as apoptosis while simultaneously promoting the expression of other genes that lead to cancer growth and metastasis.

The researchers found that CtBP can cause normal human cells to become cancerous when inserted into the cell’s DNA. In mouse models of familial adenomatous, treatment with HIPP significantly reduced intestinal polyps and increased survival while mice bred without the CtBP gene lived twice as long as those with it.

“In our experiments, HIPP acted almost as a chemical ‘silver bullet’ to prevent polyp formation, thereby reducing the risk of colon cancer,” says Grossman. “Also, we believe that anti-CtBP therapies such as HIPP may be able to complement current therapies to counter drug resistance and decrease metastasis, ultimately increasing our ability to control and cure colon cancer.”

This study is the latest in a line of research investigating CtBP by Grossman and his colleagues that began in 2010. Moving forward, they plan to continue testing derivatives of HIPP for the treatment of colon cancer and also see if their findings extend to breast, lung, ovarian and prostate cancers.

Concurrent Chemotherapy, Proton Therapy Improves Survival in Patients with Advanced Lung Cancer

For patients with advanced, inoperable stage 3 lung cancer, concurrent chemotherapy and the specialized radiation treatment, proton therapy, offers improved survival compared to historical data for standard of care, according to a new study from The University of Texas MD Anderson Cancer Center.

The research, published in JAMA Oncology, reported an overall survival (OS) of 26.5 months. In contrast, the historical OS rate with standard of care concurrent chemotherapy and traditional radiation was 16 months at the time when the study was designed.

The findings are the final results of the single institution, Phase II study and represent the longest follow-up to date of stage 3 lung cancer patients who have received proton therapy, said Joe Y. Chang, M.D., professor, Radiation Oncology and the study’s corresponding author.

Lung cancer is the leading cause of cancer death in both men and women in the U.S. According to the American Cancer Society, more than 222,500 people will be diagnosed and 155,870 will die from the disease in 2017, with the majority of patients still being diagnosed when the disease is in an advanced stage.

“Advanced lung cancer patients with inoperable disease traditionally have been treated with concurrent chemotherapy and conventional photon radiation therapy. However, the therapy can be very difficult for patients due to associated toxicities and because many patients are also dealing with comorbidities,” explained Chang.

Proton therapy is an advanced type of radiation treatment that uses a beam of protons to deliver radiation directly to the tumor, destroying cancer cells while sparing healthy tissues. Protons enter the body with a low radiation dose and stop at the tumor, matching its shape and volume or depth. They deposit the bulk of their cancer-fighting energy right at the tumor, thereby reducing the dose to cardiopulmonary structures, which impacts the toxicity, functional status, quality of life and even survival for patients, explained Chang.

“With our study, we hypothesized that proton therapy would offer a survival benefit to patients and reduce treatment-associated toxicities, which can be very serious,” he said.

The study opened at MD Anderson in 2006; in this research, Chang and his colleague report on the study’s five-year results.

For the prospective Phase II trial, 64 patients with inoperable, Stage III non-small-cell lung cancer were enrolled. The study’s primary endpoint was OS. The researchers hypothesized that the median OS would increase from historical data of 16 months on standard therapy to 24 months. Secondary endpoints included distant metastasis and local and regional recurrence rates. Toxic effects of treatment in both the acute and late settings also were analyzed.

Median follow up was 27.3 months for all patients, and 79.6 months for alive patients. At five years, the median OS was 26.5 months, and the corresponding five-year OS was 29 percent. Median progression-free survival was 12.9 months, with a five-year progression-free survival of 22 percent.

In sum, 39 patients experienced a relapse, with distant sites representing 62 percent of all recurrences. Local and regional recurrence rates were low, 16 percent and 14 percent, respectively.

Among the acute and late toxic effects diagnosed in patients were: esophagitis, pneumonitis and cardiac arrhythmia. Of note, said Chang, no patients developed the most severe, or grade five, toxicities, as seen in patients who receive standard of care.

Chang noted his study is not without limitations. Of greatest significance: the study was designed more than a decade ago. While the study’s survival, recurrence rates and toxic effects are still favorable when compared to rates associated with the most advanced traditional photon radiation therapy, intensity modulated radiation therapy (IMRT), technology to diagnose and stage the disease, as well all treatment modalities have significantly improved.

“When the study opened, PET imaging had just been approved for lung cancer staging. The image quality was poor and didn’t include a CT component in most facilities across the country,” said Chang. “Obviously, the technology has improved dramatically over the last decade and has made a significant impact on diagnosis and staging. Also, delivery of both the conventional intensity-modulated radiation therapy (IMRT) and proton therapy (IMPT), have improved, thereby reducing side effects for both treatment modalities.”

For example, MD Anderson proton therapy patients with advanced lung cancer now can receive IMPT. The technique uses an intricate network of magnets to aim a narrow proton beam at a tumor and “paint” the radiation dose onto it layer by layer. Healthy tissue surrounding the tumor is spared, and side effects are even more reduced than earlier proton delivery, said Chang. A Phase II trial studying IMPT and concurrent chemotherapy is underway. Chang also noted the advancements in cancer biology and immunotherapy and that both are important areas of research focus in combination with proton therapy.

Immune-cell numbers predict response to combination immunotherapy in melanoma

Whether a melanoma patient will better respond to a single immunotherapy drug or two in combination depends on the abundance of certain white blood cells within their tumors, according to a new study conducted by UC San Francisco researchers joined by physicians from UCSF Health. The findings provide a novel predictive biomarker to identify patients who are most likely to respond well to a combination of immunotherapy drugs known as checkpoint inhibitors — and to protect those who won’t respond from potentially adverse side effects of combination treatment.

“Combination immunotherapy is super-expensive and very toxic,” said Adil Daud, MD, director of Melanoma Clinical Research at the UCSF Helen Diller Family Comprehensive Cancer Center and senior author of the new study. “You’re putting patients at a lot of extra risk if they don’t need it, and you can adjust for that risk by knowing in advance who can benefit.”

The study, published online July 20, 2017 in Journal of Clinical Investigation Insight, describes an assay that measures the abundance of immune cells that infiltrate melanoma tumors. The findings revealed that patients who had lower levels of immune cells called T cells within their tumors benefitted most from two immunotherapy drugs in tandem. The measurements could provide clinicians with a means to predict patients who would most benefit from combination immunotherapy, the authors said.

“This is clinical research at its best,” said UCSF’s Katy Tsai, MD, a medical oncologist and lead author of the new report. “We have identified something as a predictive biomarker in melanoma, and we’re hoping to validate it in other tumor types as well.”

T cells are immune cells that patrol our body for signs of infection or other diseases, recognizing culprit cells via telltale proteins on their membranes. Our body’s normal cells carry certain proteins on their coats that act as “checkpoints,” making them invisible to T cells. But it turns out many cancer cells adopt the same trick — they cloak themselves with one of those same proteins, called PD-L1, causing T cells, which carry a complementary protein called PD-1, to mistake them as harmless. PD-L1 thus acts like a fake identification card, allowing cancer cells to live and multiply without being detected by the immune system.

Immunotherapy drugs called checkpoint inhibitors work to uncloak cancer cells by throwing a wrench in their disappearing act: these drugs block PD-L1 or PD-1, allowing T cells to recognize cancer cells as detrimental and kill them.

There are four FDA-approved checkpoint inhibitors: ipilimumab, nivolumab, pembrolizumab and atezolizumab. These drugs have been very successful in some cases, but they help only about 20 to 40 percent of patients. One of the ways doctors have improved their efficacy is by using multiple drugs at the same time. But the toxic side effects of these drugs can add up, and clinicians need to be able to correctly predict those who are most likely to respond to single drugs or combinations.

In a previous study, Daud and colleagues homed in on what makes some individuals respond well to checkpoint inhibitors that block PD-1, finding that patients whose tumors harbored high populations of T cells known as partially exhausted CD8+ cells responded well to treatment with nivolumab, an anti-PD-1 drug. Intriguingly, these cells had high levels of both PD-1 and CTLA-4, another well-known immune checkpoint protein, which is targeted by immunotherapy drugs such as ipilimumab.

In the new report, the researchers studied tumor samples from 102 melanoma patients, extracted T cells from the samples, and used cell sorting equipment to estimate the relative proportion of immune cells in the samples. The patients then underwent treatment either with only nivolumab, or with both nivolumab and ipilimumab. Finally, the researchers ran statistical tests to discover correlations among patient demographics, immune cell populations, and drug responses.

The team found that patients with high levels of exhausted T cells benefitted significantly from treatment with only a single drug. On the other hand, women and those who had liver metastases had lower number of immune cells patrolling their tumors, and responded well to the combination treatment.

“You’re pushing on two different gas pedals – PD-1 and CTLA-4,” said Daud, a member of UCSF’s Parker Institute for Cancer Immunotherapy center. “If you’re one of those patients with a low number of exhausted T cells, you have a better likelihood of benefitting from both drugs.”

The team will next explore why women have fewer T cells — and in turn, a diminished response to single immunotherapy drugs — and whether these factors could be related to age, estrogen levels, or are related to pregnancy.

The cell-counting assay developed by the researchers is time- and resource-intensive, especially because it requires fresh tumor samples and elaborate cell-sorting machines, and it is only available at UCSF. To get around these limitations, the team is now working on a more broadly applicable test that would measure the levels of PD-1 and CTLA-4 proteins — both present on T cells — in tumors and use that as a surrogate marker for immune cell count.

“In six months to a year, we should have an assay that works using fairly common, less expensive techniques,” said Daud. “And it could work on fresh, frozen or paraffin-embedded tumor blocks.” With this easier test, the researchers hope to expand their study of immune cell infiltration to other cancer types and to bigger groups of patients, both from different areas of the U.S. and internationally

Identification of PTPRZ as a drug target for cancer stem cells in glioblastoma

Glioblastoma is the most malignant brain tumor with high mortality. Cancer stem cells are thought to be crucial for tumor initiation and its recurrence after standard therapy with radiation and temozolomide (TMZ) chemotherapy. Protein tyrosine phosphatase receptor type Z (PTPRZ) is an enzyme that is highly expressed in glioblastoma, especially in cancer stem cells.

The research group of Professor Masaharu Noda and Researcher Akihiro Fujikawa of the National Institute for Basic Biology (NIBB) showed that the enzymatic activity of PTPRZ is requisite for the maintenance of stem cell properties and tumorigenicity in glioblastoma cells. PTPRZ knockdown strongly inhibited tumor growth of C6 glioblastoma cells in a mouse xenograft model. In addition, the research team discovered NAZ2329, an allosteric inhibitor of PTPRZ, in collaboration with ASUBIO Pharma Co. Ltd.. NAZ2329 efficiently suppressed stem cell-like properties of glioblastoma cells in culture, and tumor growth in C6 glioblastoma xenografts. These results indicate that pharmacological inhibition of PTPRZ is a promising strategy for the treatment of malignant gliomas.

CAR T-Cell Therapy for Leukemia Leads to Remissions in Clinical Trial

In an early-phase clinical trial of an experimental immunotherapy, researchers achieved durable molecular remissions in patients with chronic lymphocytic leukemia who had failed other treatments

Researchers at Fred Hutchinson Cancer Research Center showed about 70 percent of patients with the most common adult leukemia had their tumors shrink or disappear following an experimental chimeric antigen receptor (CAR) T-cell immunotherapy.

The researchers also found that measuring genetic traces of cancer cells taken from bone marrow biopsies might be a better indicator of prognosis than the standard lymph node scan.

The Journal of Clinical Oncology published the results online July 17 of the Phase 1/2 clinical trial, which included 24 patients with chronic lymphocytic leukemia (CLL) who had failed other treatments. Most of the patients had seen their cancer progress despite treatment with ibrutinib, a targeted cancer drug approved in 2014 for CLL by the U.S. Food and Drug Administration.

This history placed them in a high-risk group that was found in previous studies to have short survival with standard therapies.

“It was not known whether CAR T-cells could be used to treat these high risk CLL patients,” said lead author Dr. Cameron Turtle, an immunotherapy researcher at Fred Hutch. “Our study shows that CD19 CAR T-cells are a highly promising treatment for CLL patients who have failed ibrutinib.”

CD19 CAR T-cells are a type of immunotherapy in which a patient’s T cells are extracted from their blood and modified in a lab to recognize CD19, a target on the surface of leukemia cells. The engineered T cells are then infused back into the patient where they multiply and hunt down and kill cancer cells.

In CLL, bone marrow makes too many abnormal lymphocytes, which are a type of white blood cell. The American Cancer Society estimates that in the U.S., there will be about 20,000 new cases and 4,600 deaths from CLL in 2017. Tests of blood, bone marrow and lymph nodes—where lymphocytes congregate to fight infection—reveal the disease.

The 24 patients participating in the study ranged in age from 40 to 73 years, with a median age of 61. They had received a median of five other therapies with as few as three and as many as nine.

Researchers found that 17 out of 24 (71 percent) of patients saw their tumors shrink or disappear following CAR T-cell therapy using the standard measure of lymph node size by CT scans four weeks after treatment.

Of side effects of CAR-T cell therapy, 20 of the 24 patients—83 percent—experienced cytokine release syndrome (grade 1-2, 18 patients; grade 4, one patient; grade 5, one patient) and 8 patients (33 percent) developed neurotoxicity (grade 3, five patients; grade 5, one patient). For the most part the side effects were reversible, but two patients had side effects severe enough to require being admitted to the intensive care unit and one of those patients died.

 (An earlier report on trial results was presented by Turtle in December at the American Society of Hematology annual meeting.)

The new paper expands on the measures used to indicate whether the CAR T-cell treatment is working.

To take a closer look to see if any cancer cells remained after treatment, the research team analyzed samples taken from some of the patients’ bone marrow four weeks after the CAR T-cell infusion. The team used a genetic test called IGH deep sequencing, which is akin to a bar code and enables researchers to track cancer cells in the body.

Turtle and his collaborators did the sequencing analysis in 12 of the patients. Seven of the 12 patients had no malignant copies. All patients without malignant copies were alive and free of disease at a median follow-up of 6.6 months after CAR T-cell infusion.

Compared with the CT scans, having no malignant gene sequences in bone marrow following CAR T-cell therapy was a better predictor of the cancer staying at bay—known as “progression-free survival,” the researchers found.

The study is the first to suggest that deep sequencing might be a superior measure for predicting outcomes four weeks after CAR T-cell therapy for CLL.

The immunotherapy team at Fred Hutch is still enrolling eligible patients with CLL, acute lymphoblastic leukemia and non-Hodgkin lymphoma for treatment on CD19 CAR T-cell trials. The patients are seen at Seattle Cancer Care Alliance, the clinical care partner for Fred Hutch.

Fred Hutch co-authors of the paper are Kevin Hay, Laila-Aicha Hanafi, Shelly Heimfeld, Stanley R. Riddell and David G. Maloney. Other co-authors are Daniel Li, Juno Therapeutics; Sindhu Cherian, Xueyan Chen and Brent Wood, University of Washington; and Arletta Lozanski and John C. Byrd, The Ohio State University.

Funding for the project came from Juno Therapeutics, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases, Life Science Discovery Fund, the Bezos family, and the University of British Columbia.

Turtle, Maloney and Riddell receive research funding from Juno Therapeutics and are named as inventors on one or more patents or patent applications related to this work. Riddell is a co-founder of Juno Therapeutics and has equity interest in Juno Therapeutics. Li is an employee of and has equity interests in Juno Therapeutics. Fred Hutch receives research funding from Juno Therapeutics.

Radiation Therapy Prior to Surgery Reduces the Risk of Secondary Tumors in Early-Stage Breast Cancer Patients

Breast cancer patients receiving neoadjuvant radiation therapy have improved cancer-free survival over adjuvant radiation

Moffitt Cancer Center researchers launched a first of its kind study comparing the long-term benefits of radiation therapy in women with breast cancer either before surgery (neoadjuvant) or after surgery (adjuvant). Their study, published in the June 30 issue of Breast Cancer Research, found that patients who have neoadjuvant radiation therapy have a significantly lower risk of developing a second primary tumor at any site.

The majority of patients who have early stage breast cancer have surgery to remove their tumor or a complete mastectomy. Surgery is commonly followed by radiation therapy, which has been shown to increase relapse-free survival. However, in some cases, patients may require neoadjuvant radiation therapy to decrease the size of the tumor before surgery.  Currently, there are no studies that have analyzed the long-term effects of neoadjuvant radiation therapy on breast cancer patients.

Moffitt researchers compared the overall survival and the time to diagnosis of a second tumor, if any, of 250,195 breast cancer patients who received either neoadjuvant or adjuvant radiation therapy. They analyzed patient outcomes from a National Cancer Institute (NCI) registry database of cancer incidence and survival rates in the United States.  They included female patients in the analysis who were diagnosed between 1973 and 2011 with early-stage breast cancer. The analysis included 2,554 women who received localized neoadjuvant breast radiation therapy before surgery and 247,641 women who received localized adjuvant breast radiation therapy after surgery.

The researchers discovered that among the breast cancer patients who tested positive for the estrogen receptor (ER) biomarker, patients who had neoadjuvant radiation therapy had a significantly lower risk of developing a second primary tumor than patients who had adjuvant radiation therapy. This was true for patients who underwent both partial and complete mastectomies.  The researchers found that delaying surgery due to neoadjuvant radiation therapy was not a detriment to survival.

A number of recent studies have suggested that radiation therapy may re-educate and stimulate the immune system to target cancer cells. “The observed benefit of neoadjuvant radiation therapy aligns with the growing body of literature of the immune activation effects of radiation, including shrinking of untreated metastases outside the radiation field,” explained Heiko Enderling, Ph.D., associate member of Moffitt’s Integrated Mathematical Oncology Department.

T-cells lacking HDAC11 enzyme perform more effectively in destroying cancer cells

Researchers at the George Washington University (GW) Cancer Center have discovered a new role for the enzyme, histone deacetylase 11 (HDAC11), in the regulation of T-cell function.

T-cells can infiltrate tumors with the purpose of attacking the cancer cells. However, prior studies have found that the T-cells group around the tumor, but do not perform the job that they are meant to.

“The goal of the T-cell is to destroy the cancer tumor cells,” Eduardo M. Sotomayor, MD, director of the GW Cancer Center and senior author of the study, explained. “We wanted to look at and understand the mechanisms that allowed crosstalk between the tumor and the T-cells that stopped the T-cells from doing their job.”

The recent research, published in the journal Blood, centered on the discovery of “epigenetic checkpoints” in T-cell function in an effort to explain how and why these cells are modified to behave differently. The study found that when HDAC11 was removed the T-cells, they were more primed to attack the tumor.

More importantly, this research highlights that HDAC11, which was the last of 11 HDAC to be discovered, should be treated as an immunotherapeutic target.

While the study focused on the T-cells around a lymphoma tumor, this research is pertinent to all types of cancer. The goal for the team was to find a way to activate the T-cells so that they could destroy the tumor. However, the process of cell activation does need to be refined and handled carefully.

“We don’t want T-cells to be easily activated, as they can cause harm to the host — the patient. So we want to look at possible methods and therapies to activate the T-cells when they need to work,” said Sotomayor.

“The next step is to perform preclinical studies with specific inhibitors of HDAC11 alone and in tandem with other existing immunotherapies, such as anti-PD1/anti-PDL1 antibodies, in order to find the most potent combination. Our goal is to make the T-cells better at destroying cancer tumors.”

This study represents a step forward in understanding the underlying mechanisms of T-cell function and epigenetic regulation of the HDAC11 enzyme.

Genetically enhanced, cord-blood derived immune cells strike B-cell cancers

Immune cells with a general knack for recognizing and killing many types of infected or abnormal cells also can be engineered to hunt down cells with specific targets on them to treat cancer, researchers at The University of Texas MD Anderson Cancer Center report in the journal Leukemia.

The team’s preclinical research shows that natural killer cells derived from donated umbilical cords can be modified to seek and destroy some types of leukemia and lymphoma. Genetic engineering also boosts their persistence and embeds a suicide gene that allows the modified cells to be shut down if they cause a severe inflammatory response.

A first-in-human phase I/II clinical trial of these cord-blood-derived, chimeric antigen receptor-equipped natural killer cells opened at MD Anderson in June for patients with relapsed or resistant chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), or non-Hodgkin lymphoma. All are cancers of the B cells, another white blood cell involved in immune response.

“Natural killer cells are the immune system’s most potent killers, but they are short-lived and cancers manage to evade a patient’s own NK cells to progress,” said Katy Rezvani, M.D., Ph.D., professor of Stem Cell Transplantation and Cellular Therapy.

“Our cord-blood derived NK cells, genetically equipped with a receptor that focuses them on B-cell malignancies and with interleukin-15 to help them persist longer — potentially for months instead of two or three weeks — are designed to address these challenges,” Rezvani said.

Moon Shots Program funds project

The clinical trial is funded by MD Anderson’s Moon Shots Program™, designed to more rapidly develop life-saving advances based on scientific discoveries.

The chimeric antigen receptor (CAR), so-called because it’s added to the cells, targets CD19, a surface protein found on B cells.

In cell lines and mouse models of lymphoma and CLL, CD19-targeted NK cells killed cancer cells and extended survival of animals compared to simply giving NK cells alone. Addition of IL-15 to the CD19 receptor was crucial for the longer persistence and enhanced activity of the NK cells against tumor cells.

NK cells are a different breed of killer from their more famous immune system cousins, the T cells. Both are white blood cells, but T cells are highly specialized hunters that look for invaders or abnormal cells that bear a specific antigen target, kill them and then remember the antigen target forever.

Natural killers have an array of inhibitory and activating receptors that work together to allow them to detect a wider variety of infected, stressed or abnormal cells.

“By adding the CD19 CAR, we’re also turning them into guided missiles,” said Elizabeth Shpall, M.D., professor of Stem Cell Transplantation and Cell Therapy.

Using a viral vector, the researchers transduce NK cells taken from cord blood with the CD19 CAR, the IL-15 gene, and an inducible caspase-9-based suicide gene.

Cell line tests found the engineered NK cells to be more efficient killers of lymphoma and CLL cells, compared to unmodified NK cells, indicating the engineered cells’ killing was not related to non-specific natural killer cell cytotoxicity.

Another experiment showed the engineered cord blood NK cells killed CLL cells much more efficiently than NK cells taken from CLL patients and engineered, highlighting the need to transplant CAR-engineered NK cells from healthy cord blood rather than use a patient’s own cells.

Suicide gene to counter cytokine release syndrome

Mouse model lymphoma experiments using a single infusion of low dose NK cells resulted in prolongation of survival. At a higher, double dose, none of the mice treated with the CD19/IL-15 NK cells died of lymphoma, with half surviving for 100 days and beyond. All mice treated with other types of NK cells died by day 41.

A proportion of mice treated with the higher dose of engineered NK cells died of cytokine release syndrome, a severe inflammatory response that also occurs in people treated with CAR T cells.

To counteract this toxicity, the researchers incorporated a suicide gene (iC9) that can be activated to kill the NK cells by treatment with a small-molecule dimerizer. This combination worked to swiftly reduce the engineered NK cells in the mouse model.

Subsequent safety experiments were conducted in preparation for the clinical trial. Rezvani, the principal investigator of the clinical trial, says the protocol calls for vigilance for signs of cytokine release syndrome, treatment with steroids and tocilizumab for low-grade CRS with AP1903 added to activate the suicide gene for grade 3 or 4 CRS.

NK CARs available off the shelf

T cells modified with chimeric antigen receptors against CD19 have shown efficacy in clinical trials. In these therapies, a patient’s own T cells are modified, expanded, and given back to the patient, a process that takes weeks. Finding a matched donor for T cells would be a challenge, but would be necessary because unmatched T cells could attack the recipient’s normal tissue – graft vs. host disease.

Rezvani and Shpall have given patients cord-blood derived NK cells in a variety of clinical trials and found that they do not cause graft vs. host disease, therefore don’t have to be matched. NK cells can be an off-the-shelf product, prepared in advance with the necessary receptor and given promptly to patients.

“CAR NK cells are scalable in a way that CAR T cells are not,” Rezvani noted.

A strength of T cells is the development of memory cells that persist and repeatedly attack cells bearing the specific antigen that return. NK cells do not seem to have a memory function, but Rezvani says the experience of the longer-lived mice, which are now more than a year old, raises the possibility that a prolonged NK cell attack will suffice.

Shpall, Rezvani and colleagues are developing cord blood NK CARs for other targets in a variety of blood cancers and solid tumors.

MD Anderson and the researchers have intellectual property related to the engineered NK cells, which is being managed in accordance with the institution’s conflict-of-interest rules.

Shpall founded and directs MD Anderson’s Cord Blood Bank, originally established to provide umbilical cord blood stem cells for patients who need them but cannot get a precise donor match. Donated by mothers who deliver babies at seven Houston hospitals and two others from California and Michigan, the bank now has 26,000 cords stored. MD Anderson researchers pioneered the extraction and expansion of NK cells from umbilical cords.

Risk-reducing mastectomy questioned for BRCA mutation carriers with prior ovarian cancer

Mutations in the BRCA gene correspond to a higher lifetime risk of developing breast and ovarian cancers, and many women who carry these mutations consider undergoing mastectomy or removal of the ovaries and fallopian tubes as preventive measures.

But for the subset of women with BRCA mutations who have already had ovarian cancer, risk-reducing mastectomy might not be worth the price tag. New research from the Duke Cancer Institute finds that for many women in this unique group, prophylactic mastectomy does not produce a substantial survival gain and is not cost-effective.

The finding is especially noteworthy because of updated National Comprehensive Cancer Network guidelines recommending that many women with ovarian cancer be considered for genetic testing regardless of family history. Now, more than ever before, some women with ovarian cancer are also learning that they carry a BRCA mutation.

“Risk-reducing mastectomy is costly and can require many months of follow-up and recovery,” said Charlotte Gamble, M.D., the study’s lead author and a resident physician at Duke University School of Medicine. “Our results emphasize that prophylactic mastectomy should be used selectively in women with both a BRCA mutation and a history of ovarian cancer.”

In the study, published online July 11 in the journal Annals of Surgical Oncology, Gamble and co-researchers constructed a statistical model comparing risk-reducing mastectomy to breast cancer screening, including mammogram and MRI. The model incorporated clinical factors such as the age at ovarian cancer diagnosis, time between ovarian cancer diagnosis and risk-reducing mastectomy, BRCA mutation status, cancer survival rates and treatment costs. Risk-reducing mastectomy was compared to breast cancer screening performed every six months following ovarian cancer diagnosis.

The study’s authors also considered a cost-effectiveness measurement called the incremental cost effectiveness ratio. Healthcare interventions where this ratio is less than $100,000 per year of life saved are commonly considered cost-effective in medical literature. The authors used the same threshold in this study.

According to the authors’ analysis, the benefit of risk-reducing mastectomy over screening alone largely depended on the patient’s age at the time of her ovarian cancer diagnosis and time to mastectomy:

For women diagnosed at any age with BRCA 1 and 2 gene mutations and within the first four years after ovarian cancer diagnosis, mastectomy was associated with a negligible gain in survival and was therefore not found to be cost-effective;

For women diagnosed at age 60 or older, regardless of time since ovarian cancer diagnosis, the gain in survival months was also negligible and the procedure was not cost-effective;

For women diagnosed at age 40 to 50 with BRCA 1 and 2 mutations and at least five years after an ovarian cancer diagnosis, the procedure was associated with a survival benefit of two to five months compared to screening and found to be cost-effective.

“Our study provides clarity on how a woman’s age and timing of a risk-reducing mastectomy after an ovarian cancer diagnosis impact the benefit of this procedure,” Gamble said. “Within the first five years, nobody benefited from risk-reducing mastectomy and after that threshold, survival gains were seen mostly in the youngest, healthiest ovarian cancer patients.”

“There is no right or wrong answer on how to manage breast cancer risk in this unique population,” added senior author Rachel Greenup, M.D., assistant professor of surgery at Duke. “However, we hope that our findings provide guidance to women and their doctors deciding if and when prophylactic mastectomy is beneficial following ovarian cancer treatment.”

Personal neoantigen vaccine prompts strong anti-tumor response in patients, study shows

A personal cancer treatment vaccine that targets distinctive “neoantigens” on tumor cells has been shown to stimulate a potent, safe, and highly specific immune anti-tumor response in melanoma patients, report scientists from Dana-Farber Cancer Institute and the Broad Institute of MIT and Harvard.

The study, published online by Nature “provides proof-of-principle that a personal vaccine tailored to a patient’s tumor can be produced and generates highly specific responses to that patient’s tumor after vaccination,” said the researchers, led by Catherine J. Wu, MD, senior author of the report. She is a researcher at Dana-Farber, the Broad Institute, and Harvard Medical School.

The scientists said that while most therapies are based on the on-size-fits-all model of medicine, “we’ve long recognized in cancer that every patient’s tumor is different. With recent advances in technology, it’s now becoming possible to create a therapy that’s suited to target an individual’s tumor.”

The researchers say the results warrant further development of neoantigen vaccines, both alone and in combination with other immunotherapy weapons such as checkpoint inhibitors. The vaccine, known as NeoVax, prompted strong activity by the patients’ immune systems while causing negligible side effects.

First authors of the report are Patrick A. Ott, MD, PhD, and Zhuting Hu, PhD, of Dana-Farber. Other senior authors include Nir Hacohen, PhD, of the Broad Institute and Massachusetts General Hospital, Edward Fritsch, PhD, formerly of Dana-Farber and now at Neon Therapeutics in Cambridge, Mass, and Eric Lander, PhD, of the Broad Institute.

Antigens are molecules that are displayed on the surface of cells and stimulate the immune system. Neoantigens are molecules on cell’s surfaces that are produced by DNA mutations that are present in cancer cells but not in normal cells, making neoantigens ideal targets for immune therapy against cancer, say the scientists. The vaccines used in the phase I trial contained up to 20 neoantigens, derived from an individual patient’s tumor. The vaccines were administered to patients to train their immune system to recognize these neoantigens, with the goal of stimulating the immune system to destroy the cancer cells that display them.

While other immunotherapies, such as checkpoint inhibitor drugs, also trigger immune responses against cancer neoantigens, they are not designed to be specific. They can also induce responses against normal tissue antigens, leading the immune system to attack normal tissues and cause toxicity in a subset of patients. The researchers found that the personal vaccine induced a focused T cell response against several tumor neoantigens, beyond what is normally seen in response to existing immunotherapies.

The vaccine was administered to six patients with melanoma whose tumors had been removed by surgery and who were considered at high risk for recurrence. The vaccinations were started at a median of 18 weeks after surgery. At a median of 25 months after vaccination, four of the six patients showed no evidence of cancer recurrence. In the other two patients, whose cancer had spread to their lungs, the disease recurred after vaccination. At that point, they began treatment with the drug pembrolizumab, which inhibits the PD-1 immune checkpoint. Both patients had complete resolution of their tumors and remain free of disease according to imaging scans.

The study results suggest, that a personalized neoantigen vaccine can potentially overcome two major hurdles in cancer therapy.

One is the heterogeneity of tumors – the fact that they are made up of cells with a variety of different traits, which often allows cancers to evade drugs targeted to malignant cells having a single genetic abnormality. The vaccine, because it contains many different neoantigens from the tumor, targets multiple genetic types of tumor cells. Wu added that in this respect, the response generated by a neoantigen vaccine is similar to the new wave of combination therapies, which are showing more promise in treating cancers that typically develop resistance to single drugs. “We are leveraging the immune system’s natural ability to detect and attack many target antigens, as it does every time we get an infection,” she said.

A second hurdle in cancer is to generate an immune response sharply focused on cancer cells while avoiding normal cells and tissues. This aim was achieved by the vaccine, which appeared to have few “off-target” effects, causing only flu-like symptoms, fatigue, rashes, and irritation at the site of the vaccine injection, according to the report.

Despite decades of attempts to develop effective cancer treatment vaccines, they have mostly failed at producing potent antitumor immune responses. The study authors say that is because these vaccines have generally been made with tumor antigens that are too similar to antigens on normal cells: as a result, the body generates a weaker immune response to avoid harming normal cells, a process called immune tolerance. By contrast, the neoantigen vaccine is custom-made for each patient using antigens produced by mutations unique to the patient’s cancer and only present on cancer cells, thus bypassing the nature immune tolerance process.

To create the vaccine, samples of a patient’s tumor and normal DNA from the patient’s blood underwent whole-exome sequencing to reveal mutations present only in the tumor’s genetic program. Because some mutations are present in the DNA but the gene is not made into RNA and protein, the researchers used RNA sequencing to identify mutations that caused the production of a mutated RNA, which is then normally translated into a protein.

Since T cells can only recognize neoantigens that are “presented” to them by HLA molecules of the immune system, a key step in making the vaccine is using computer algorithms to predict which neoantigen peptides will bind strongly to the HLA molecules for recognition by T cells. Algorithms, such as NetMHC, have been developed in recent years, making it feasible to select HLA-binding neoantigen peptides for the vaccine. Applying this tool to the six patients’ tumor samples yielded dozens of unique neoantigens for each patient’s personal vaccine.

Finally, the selected neoantigen peptides were synthesized and mixed with an adjuvant – a biochemical substance that helps to jump-start the immune response. The vaccine was then injected under the skin of the patient, with five priming doses followed by two booster doses of the vaccine.

The vaccine was aimed at generating responses to the neoantigens from T cells of two kinds – CD8+ killer cells and CD4+ helper cells. When the team monitored the vaccine’s effects on the immune system in each patient, they found that both T cell types had indeed been activated by the vaccine and could recognize the neoantigens bound to HLA molecules. Most importantly, many of the T cells were able to recognize the tumor cells directly, demonstrating that the vaccine had triggered a tumor-specific immune response that could target the patient’s tumor.

“Future neoantigen vaccine trials will recruit more patients with advanced disease to test the efficacy of the vaccine, take advantage of improved methods for predicting antigen presentation to boost the number of effective neoantigens and test for synergy with checkpoint blockade and other immunotherapeutics,” the scientists said. “If successful in subsequent trials, a personal vaccine has the potential to be applied to any cancer that harbors a sufficient numbers of neoantigens for vaccination.”

FDA Halts Three Multiple Myeloma Studies Evaluating Merck’s KEYTRUDA®

Merck known as MSD outside the United States and Canada, today announced that the U.S. Food and Drug Administration (FDA) has placed a clinical hold on KEYNOTE-183, KEYNOTE-185 and KEYNOTE-023, three combination studies of KEYTRUDA® (pembrolizumab), the company’s anti-PD-1 therapy, in the blood cancer multiple myeloma.

This decision follows a review of data by the Data Monitoring Committee in which more deaths were observed in the KEYTRUDA arms of KEYNOTE-183 and KEYNOTE-185 and which led to the pause in new patient enrollment, as announced on June 12, 2017. The FDA has determined that the data available at the present time indicate that the risks of KEYTRUDA plus pomalidomide or lenalidomide outweigh any potential benefit for patients with multiple myeloma. All patients enrolled in KEYNOTE-183 and KEYNOTE-185 and those in the KEYTRUDA/lenalidomide/dexamethasone cohort in KEYNOTE-023 will discontinue investigational treatment with KEYTRUDA.

This clinical hold does not apply to other studies with KEYTRUDA.

The following studies have been placed on full clinical hold:

  • KEYNOTE-183: “A Phase III study of Pomalidomide and low-dose Dexamethasone with or without Pembrolizumab (MK3475) in refractory or relapsed and refractory Multiple Myeloma (KEYNOTE-183).”
  • KEYNOTE-185: “A Phase III study of Lenalidomide and low-dose Dexamethasone with or without Pembrolizumab (MK3475) in newly diagnosed and treatment naïve Multiple Myeloma (KEYNOTE-185).”

The following study has been placed on partial clinical hold:

  • KEYNOTE-023 Cohort 1: “A Phase I Multi-Cohort Trial of Pembrolizumab (MK-3475) in Combination with Backbone Treatments for Subjects with Multiple Myeloma (KEYNOTE 023).” Cohort 1 of KEYNOTE-023 evaluated KEYTRUDA (pembrolizumab) in combination with lenalidomide and dexamethasone in patients who received prior anti-multiple myeloma treatment with an immunomodulatory (IMiD) treatment (lenalidomide, pomalidomide or thalidomide).

“Patient safety is Merck’s primary concern, and we are grateful to the study investigators and patients involved in these studies for their commitment to this important research,” said Dr. Roger M. Perlmutter, president, Merck Research Laboratories. “Merck’s development program for KEYTRUDA, spanning more than 30 different tumor types, has one priority: helping patients suffering from cancer.”

For more information about Merck’s oncology clinical trials, visit www.merck.com/clinicaltrials.

Promising new therapeutic approach for debilitating bone disease

An Australian-led research team has demonstrated a new therapeutic approach that can re-build and strengthen bone, offering hope for individuals with the debilitating bone cancer, multiple myeloma.

The findings were published today in the medical journal Blood, and were presented at an international meeting of bone biology experts in Brisbane earlier this month.

The researchers tested a new type of treatment that specifically targets a protein called sclerostin, which in healthy bones is an important regulator of bone formation. Sclerostin halts bone formation, and the researchers speculated that if they could inhibit the action of sclerostin, they could reverse the devastating bone disease that occurs with multiple myeloma.

Dr Michelle McDonald and Professor Peter Croucher, of the Bone Biology Division of the Garvan Institute of Medical Research in Sydney, led the study.

“Multiple myeloma is a cancer that grows in bone, and in most patients it is associated with widespread bone loss, and recurrent bone fractures, which can be extremely painful and debilitating,” says Dr McDonald.

“The current treatment for myeloma-associated bone disease with bisphosphonate drugs prevents further bone loss, but it doesn’t fix damaged bones, so patients continue to fracture. We wanted to re-stimulate bone formation, and increase bone strength and resistance to fracture.”

The new therapeutic approach is an antibody that targets and neutralises sclerostin, and in previous clinical studies of osteoporosis, such antibodies have been shown to increase bone mass and reduce fracture incidence in patients.

The researchers tested the anti-sclerostin antibody in mouse models of multiple myeloma, and found that not only did it prevent further bone loss, it doubled bone volume in some of the mice.

Dr McDonald says, “When we looked at the bones before and after treatment, the difference was remarkable – we saw less lesions or ‘holes’ in the bones after anti-sclerostin treatment.

“These lesions are the primary cause of bone pain, so this is an extremely important result.”

The researchers have a biomechanical method to test bone strength and resistance to fracture, and found that the treatment also made the bones substantially stronger, with more than double the resistance to fracture observed in many of the tests.

They then combined the new antibody with zoledronic acid, a type of bisphosphonate drug, the current standard therapy for myeloma bone disease.

“Bisphosphonates work by preventing bone breakdown, so we combined zoledronic acid with the new anti-sclerostin antibody, that re-builds bone. Together, the impact on bone thickness, strength and resistance to fracture was greater than either treatment alone,” says Dr McDonald.

The findings provide a potential new clinical strategy for myeloma. While this disease is relatively rare, with approximately 1700 Australians diagnosed every year, the prognosis is extremely poor, with less than half of those diagnosed expected to survive for more than five years.

Prof Croucher, Head of the Bone Biology Division at Garvan, says that preventing the devastating bone disease of myeloma is critical to improve the prognosis for these people.

“Importantly, myelomas, like other cancers, vary from individual to individual and can therefore be difficult to target. By targeting sclerostin, we are blocking a protein that is active in every person’s bones, and not something unique to a person’s cancer. Therefore, in the future, when we test this antibody in humans, we are hopeful to see a response in most, if not all, patients,” Prof Croucher says.

“We are now looking towards clinical trials for this antibody, and in the future, development of this type of therapy for the clinical treatment of multiple myeloma.

“This therapeutic approach has the potential to transform the prognosis for myeloma patients, enhancing quality of life, and ultimately reducing mortality.

“It also has clinical implications for the treatment of other cancers that develop in the skeleton.”

Study shows biomarkers can predict which ER-positive breast cancer patients respond best to first-line therapy

Two challenges in treating patients with estrogen-positive breast cancer (ER+) have been an inability to predict who will respond to standard therapies and adverse events leading to therapy discontinuation. A study at The University of Texas MD Anderson Cancer Center revealed new information about how the biomarkers retinoblastoma protein (Rb) and cytoplasmic cyclin E could indicate which patients will respond best to current first-line therapies.

The study also discovered that combining the current therapy with autophagy inhibitors will result in using one-fifth of the dosage of the standard treatment, which could significantly reduce side effects associated with this therapy. Findings were published in the June 27 issue of Nature Communications.

Standard treatment, consisting of palbociclib, often has adverse side effects and not all ER+ patients respond to the therapy. Palbociclib inhibits proteins called CDK4 and CDK6 (CDK4/6) and tumor cells escape this inhibition by activating autophagy, a process allowing cancer cells to thrive even when starved of nutrients. By combining palbocicilb with autophagy inhibitors in cells that express normal Rb and nuclear cyclin E, the dose of palbociclib was significantly reduced.

Khandan Keyomarsi, Ph.D., professor of Experimental Radiation Oncology, led a team that demonstrated how CDK4/6 and autophagy inhibitors synergistically induce cell senescence in Rb-positive cytoplasmic cyclin E-negative cancers. CDK4/6 inhibitors are approved by the Food and Drug Administration (FDA).

“Our findings could impact the majority of ER+ and HER2-negative breast cancers accounting for about 60 percent of advanced breast cancers,” said Keyomarsi. “We demonstrated for the first time evidence that Rb and cytoplasmic cyclin E status have a very strong effect on predicting response to the current standard first-line therapy for this population of patients, hormonal therapy plus palbociclib.We also discovered that by inhibiting the pathway such as autophagy that causes tumor cells to escape palbociclib growth inhibition, CDK4/6 inhibitor was more effective.”

Deregulation of cell cycle checkpoint proteins, such as CDK4/6, is a key hallmark of cancer, resulting in uncontrolled cellular growth and tumor formation. Some CDK4/6 inhibitors, including palbociclib, ribociclib and abemaciclib, have shown potential in pre-clinical and clinical studies in numerous solid tumors. Palbociclib has demonstrated benefits in Phase II and III trials in advanced ER+ breast cancers, doubling progression-free survival compared to drugs such as letrozole or fulvestrant, and is currently being evaluated clinically in other solid tumors.

“Data provided through The Cancer Genome Atlas revealed alterations in the CDK4/6/cyclin D pathway in about 35 percent of the patients, making them an ideal population for targeting CDK4/6,” said Keyomarsi. “Our study revealed that inhibition of CDK4/6 and autophagy pathways cooperate to induce sustained growth inhibition and senescence in vitro and in vivo, in breast and other solid tumors and showed how autophagy inhibition can significantly decrease the dose of palbociclib required to treat breast cancer patients. We believe this new strategy can improve the efficacy of other CDK4/6 inhibitor treatments like ribociclib and abemaciclib.”

The team’s findings indicated how Rb and cyclin E status predicts response to a combination of CDK4/6 and autophagy inhibition in pre-clinical models and that autophagy blockade is successful in reversing resistance to palbociclib.

“Palbociclib resistance is a significant limitation of this treatment which is not curative and does not prolong survival even though transient responses and prolongation of response have formed the basis of FDA approval,” said Keyomarsi. “Our study provides evidence that models of hormone receptor-negative cancer and even non-breast cancer malignancies can respond to the combination of palbociclib and autophagy inhibition, when selected based on Rb and cyclin E isoform status, representing a completely new therapeutic opportunity for these cancers.”

Keyomarsi and colleagues anticipate future clinical studies based on this pre-clinical and clinical evidence with the aim of developing translational and clinical applications.

Combination approach improves power of new cancer therapy

An international research team has found a way to improve the anti-cancer effect of a new medicine class called ‘Smac mimetics’.

The team discovered how a protein called MK2 helps to keep cancer cells alive, making them resistant to the anti-cancer effects of Smac mimetics. The findings provide a rationale for combining inhibitors of MK2 with Smac mimetics as a potentially powerful new combination therapy for cancers with few treatment options, such as acute myeloid leukaemia (AML).

The research, recently published in the journal Molecular Cell, was the outcome of a research collaboration between Dr Najoua Lalaoui, Professor John Silke and colleagues at the Walter and Eliza Hall Institute, Australia; Professor Pascal Meier and colleagues at the Institute of Cancer Research, UK; and Professor Manolis Pasparakis and colleagues at the Cluster of Excellence CECAD at University of Cologne, Germany.

Dr Lalaoui said the research helped to advance her team’s previous discovery that combining the Smac mimetic agent birinapant with another new class of anti-cancer agents, called p38 inhibitors, could offer a new approach to treating AML.

“We knew these two agents could be combined, but didn’t fully understand the how they worked together at the molecular level,” Dr Lalaoui said.

“This latest study has pinpointed the MK2 protein as critical for the combination of Smac mimetics and p38 inhibitors to have a potent anti-cancer effect. As well as understanding our previous discovery better, it also highlights MK2 as an exciting new target for anti-cancer therapies, particularly in combination with Smac mimetics.”

Professor Silke said the research was part of a growing trend in the field, taking ‘rational’ approaches to treating cancer better, particularly through selecting combinations of anti-cancer agents.

“By understanding precisely which molecules are helping cancer cells to survive and evade treatment, we can develop smarter ways to kill these cells,” Professor Silke said.

“In the first place, the rational development of combination therapies has the potential to provide new treatments for cancers, such as AML, that have previously had poor outcomes.”

He said another potential benefit of combined anti-cancer therapies could be using each agent at lower doses.

“With a combined approach, the agents could still kill the cancer cell but with fewer harmful side effects on healthy tissues. Our goal is to develop cancer treatments that are both safer and more powerful than are currently available” Professor Silke said.

Custom built molecule shows promise as anti-cancer therapy

Scientists at the University of Bath funded by Cancer Research UK have custom-built a molecule which stops breast cancer cells from multiplying in laboratory trials, and hope it will eventually lead to a treatment for the disease.

But perhaps even more importantly the method they used to create the molecule has potential to be applied to develop new treatments for a wide range of cancers and other diseases.

The team, from the Department of Biology & Biochemistry, working with colleagues at the University of Queensland in Australia and the University of Bristol, modified a protein which can interfere with cell multiplication in many cancers, including breast cancer, by binding with another protein and rendering it inactive.

They took a small piece of the protein, called a peptide, that is known to be important in binding, and modified it to retain the structure otherwise lost when cut out. The modification has the additional advantage of protecting the peptide from being broken down within cells. The resulting molecule still binds to its target protein and inhibits cancer cell multiplication, but crucially can travel across cell membranes to get at it. The full-sized proteins, which the peptides are taken from, are usually too large to protect from breakdown or to cross protective cell membranes so this removes a literal barrier to developing treatments.

The study is published in the journal ACS Chemical Biology

Dr Jody Mason, one of the lead researchers on the project, said: “Peptides have the potential to be incredibly potent drugs which are exquisitely specific for their target. However they are easily broken down in the body, much like when we eat a steak. We have modified the peptides so that they retain the structure they have within the full-size protein and can therefore bind to the target “

Professor David Fairlie, from the University of Queensland added “This is a particularly challenging cancer target involving intertwined proteins and large surfaces that must be blocked. International collaborations like this one have the potential to combine resources and scientific skills from multiple disciplines to conquer difficult problems in targeting human disease.”

Dr Justine Alford, Cancer Research UK’s senior science information officer, said: “This early study may have laid the groundwork for a potential new treatment for certain cancers by creating a sophisticated designer molecule that can effectively block a cancer-fuelling target in cells.

“Cancer survival is improving, but people still die from their disease, so we need to develop innovative ways such as this that could help more people survive in the future.” The team now intend to continue to work on the molecule to improve its stability, with a long-term view to it eventually becoming a cancer drug, although this is still years away.

They are also interested in finding other candidate peptides for similar trials.

The researchers believe that other small peptides are a promising avenue of research to create new treatments for different types of cancer, and potentially other diseases such as Alzheimer’s disease

New inhibitor drug shows promise in relapsed leukemia

A new drug shows promise in its ability to target one of the most common and sinister mutations of acute myeloid leukemia (AML), according to researchers at the Perelman School of Medicine at the University of Pennsylvania and Penn’s Abramson Cancer Center. The Fms-like tyrosine kinase 3 (FLT3) gene mutation is a known predictor of AML relapse and is associated with short survival. In a first-in-human study, researchers treated relapsed patients with gilteritinib, an FLT3 inhibitor, and found it was a well-tolerated drug that led to frequent and more-sustained-than-expected clinical responses, almost exclusively in patients with this mutation. They published their findings today in The Lancet Oncology.

FLT3 is one of the most commonly mutated genes in AML patients. FLT3 mutations are found in about 30 percent of patients’ leukemia cells. Clinically, these mutations are associated with aggressive disease that often leads to rapid relapse, after which the overall survival is an average of about four months with current therapies. To avoid relapse, oncologists often recommend the most aggressive chemotherapy approaches for patients with FLT3 internal tandem duplication (FLT3-ITD), including marrow transplantation. But even that cannot always stave off the disease.

The FLT3 gene is present in normal bone marrow cells and regulates the orderly growth of blood cells in response to daily demands. When the gene is mutated in a leukemia cell, however, the mutated cells grow in an uncontrolled manner unless the function of FLT3 is turned off.

“Other drugs have tried to target these mutations, and while the approach works very well in the laboratory, it has proven very challenging to develop FLT3 inhibitors in the clinic for several reasons,” said Alexander Perl, MD, MS, an assistant professor of Hematology Oncology in Penn’s Abramson Cancer Center and the study’s lead author. “First, we’ve learned it takes unusually potent inhibition of the FLT3 target to generate clinical responses. Second, many of these drugs are not selective in their activity against FLT3. When they target multiple kinases, it can lead to more side-effects. That limits whether you can treat a patient with enough drug to inhibit FLT3 at all. Finally, with some FLT3 inhibitors, the leukemia adapts quickly after response and cells can develop new mutations in FLT3 that don’t respond to the drugs at all. So ideally, you want a very potent, very selective, and very smartly designed drug. That’s hard to do.”

For this phase 1/2 clinical trial, Perl and his team evaluated the drug gilteritinib – also known as ASP2215 – at increasing doses in patients whose AML had relapsed or was no longer responding to chemotherapy. The team focused on dose levels at 80mg and above, which were associated with more potent inhibition of the FLT3 mutation and higher response rates. They found these doses were also associated with longer survival. Of the 252 patients on this study, 67 were on a 120mg dose and 100 were on a 200mg dose. Seventy-six percent (191) of the patients on the trial had a FLT3 mutation. Overall, 49 percent of patients with FLT3 mutations showed a response. Just 12 percent of patients who didn’t have the mutation responded to the drug.

“The fact that the response rate tracked with the degree of FLT3 inhibition and was so much lower among patients who did not have an FLT3 mutation gives us confidence that this drug is hitting its target,” Perl said.

In leukemia cells, FLT3 itself can mutate again to a form called a D835 mutation that is resistant to several FLT3 inhibitors treatments. Gilteritinib, however, remains active against D835 mutations in laboratory models of leukemia. Clinical response rates from the trial appeared to be the same, whether patients had a FLT3-ITD alone or both a FLT3-ITD and a D835 mutation. The response rates also were similar in patients in whom gilteritinib was their first FLT3 inhibitor and those who previously were treated with other FLT3 inhibitors.

The drug was also generally well-tolerated. The three most common side effects attributed to the drug were diarrhea in 41 patients (16 percent), fatigue in 37 (15 percent), and abnormal liver enzyme tests in 33 (13 percent). These generally were mild in severity and discontinuation of gilteritinib for side effects was uncommon (25 patients, 10 percent).

“These look like data you want to see for a drug to eventually become a standard therapy,” Perl said, though he noted more research will be necessary.

A new multicenter trial, which compares gilteritinib to standard chemotherapy in patients with FLT3 mutations who relapsed or did not respond to initial therapy, is now underway, and Penn’s Abramson Cancer Center is one of the sites.

There are also studies underway that give the drug in combination with frontline chemotherapy and as an adjunct to bone marrow transplantation in hopes of preventing relapse altogether.

A patent study on the great new hope emerging from marine derived anticancer drugs

Microtubule dynamics govern crucial cellular functions and this is why microtubules are one of the most attractive anticancer drug targets. Microtubule targeting agents (MTAs) have the ability to treat a wide range of cancers. However, drug induced cytotoxicity and adverse side effects have hindered their development. Another major setback is multiple drug resistance in tumor cells. These limitations have prompted the need to develop novel MTAs from alternative sources, with better therapeutic efficacies. Recently, MTAs from marine sources have grabbed much attention due to their unique tubulin binding features and remarkable ability to reduce tumor progression.

The authors have summarized some of the most promising marine derived MTAs by systematically searching patent databases such as USPTO, Espacenet and WIPO for recent patents published from 2006 up to 2016. After a critical data analysis, only those patents focusing on the chemical synthesis and/or modifications of marine derived MTAs along with a significant demonstration of their in vitro and/or in vivo activity have been reviewed.

The survey of recent patents revealed that chemically modified versions of marine derived MTAs, overcoming drug resistance and their novel combination therapies increasing the overall efficacy, have positioned them as future anticancer blockbusters. Of particular interest are dolastatin, laulimalide, peloruside, hemiasterlin, halichondrin, eribulin mesylate, discodermolide, dictyostatin, cryptophycin and their analogs which have significant antiproliferative potency against a wide array of cancers and are also able to overcome multidrug resistance. A deeper understanding of the molecular mechanisms behind the specific drug interactions and of microtubule molecular biology in general, combined with innovative therapeutic regimen would lead to major advances in the field of cancer therapy.

Inhibitor drug improves overall survival in older radioiodine resistant thyroid cancer

The drug lenvatinib can significantly improve overall survival rates in a group of thyroid cancer patients whose disease is resistant to standard radioiodine treatment, according to new research from the Perelman School of Medicine at the University of Pennsylvania. The study, published today in the Journal of Clinical Oncology, is the first to show lenvatinib has a definitive impact on overall survival (OS). Researchers found OS improves in patients older than 65 years of age and that the drug is well-tolerated.

“Due to limitations of study design, it has been hard to prove that multikinase inhibitors improve overall survival, although we have suspected it,” said the study’s lead author Marcia Brose, MD, PhD, an associate professor of Otorhinolaryngology and a member of Penn’s Abramson Cancer Center. “These findings put that doubt to rest for the group of patients over 65 treated with lenvatinib.”

Most cases of differentiated thyroid cancer (DTC) are treated with radioiodine therapy. Since the thyroid absorbs nearly all of the iodine in the human body, radioactive iodine given to a patient will concentrate in thyroid cancer cells, killing them with little effect on the rest of the body. The treatment can be curative, but about 15 percent of DTC patients have cancers that are resistant to the therapy.

Levatinib is one of two first-line therapies approved by the U.S. Food and Drug Administration for patients who are resistant to radioiodine treatment. The drug is a multi- kinase inhibitor (MKI) — meaning it targets the specific enzymes that are required for growth in DTC.

“It was approved based on previous trials that showed it had a benefit for progression-free survival, but until now, nobody has shown it also has a benefit for overall survival,” Brose said.

Brose and her team participated in the SELECT trial to study the effects of levatinib on DTC, and Brose directed the further analysis published in this report which specifically looked at OS and safety of lenvatinib in younger and older patients. Patients were divided into two groups: Those 65 or younger, and those older than 65. The median age of the younger group was 56. For the older group, it was 71. Each group contained patients on the drug and patients receiving a placebo.

Researchers found significant differences in overall survival between those on the drug and those on the placebo in the older age group. Among the older cohort, those on the placebo had an OS of 18.4 months. For patients receiving the drug, OS was not reached, but confidence intervals show the expected survival would exceed 22 months. In the younger cohort, overall survival was not reached for either group.

“There’s a belief that these drugs should be withheld from older patients due to concerns about toxicity and other medical concerns, but our results show just the opposite,” Brose said. “Not only do older patients benefit from these drugs, but they generally tolerate them well.”

Brose says the results of this study can have an immediate impact in clinical care, and several other studies are ongoing to find new uses for lenvatinib in other types of thyroid cancer.

Talking Breast Cancer for Men’s Health Awareness Week

Males account for less than 1 percent of all breast cancer cases in the United States. In 2017, an estimated 2,470 American men will be diagnosed with the disease; 460 will die.

While rare among men, breast cancer symptoms, diagnosis and survival are similar for both genders. Men experience many of the same primary symptoms or signs of breast cancer: a lump or swelling in the chest area or new irregularities on the skin or nipples, such as redness, scaliness or puckering. Because male breasts generally have less tissue than female, it’s easier to detect lumps. However, some men with breast cancer never display obvious signs of the disease or fail to notice them.

“Both men and women benefit from being aware of their bodies and seeking care with their primary care providers for changes,” said Richard Schwab, MD, oncologist with Moores Cancer Center at UC San Diego Health.

The earlier breast cancer is detected, the better the chances of recovery and survival. In the earliest stages, the five-year survival rate (the percentage of people who live at least five years after diagnosis, excluding other causes of death) is 99 percent. If the cancer has spread to local lymph nodes, the 5-year survival rate drops to 85 percent. If the cancer metastasizes to more distant parts of the body, the rate falls to 27 percent.

As with women, men have a higher risk of developing cancer if they have a family history of breast disease or a mutation in a breast cancer risk gene, such as BRCA1 or BRCA2. In addition, age, high levels of radiation, elevated levels of estrogen (which can be caused by genetic conditions), other diseases, some kinds of medical treatment and lifestyle can increase a man’s risk of breast cancer.