Fred Hutch researchers engineer complex immunotherapy that may target relapsing leukemia

Researchers at Fred Hutchinson Cancer Research Center and the University of Washington have developed a novel way to genetically engineer T cells that may be effective for treating and preventing leukemia relapse.

The findings, published online in the journal Blood, provide the basis for launching a first-in-human clinical trial of this new immunotherapy, which relies on engineered T-cell receptors, or TCRs. This immunotherapy represents a different method of genetic engineering than the CAR T-cell therapies that were recently approved by the U.S. Food and Drug Administration.

Relapse occurs in about one-third of patients with acute leukemia who undergo stem cell transplantation to rebuild cancer-free blood cells, and more than 90 percent of these patients die after an average survival of about four months.

“New therapies are desperately needed to prevent and treat relapse of leukemia in patients who have undergone hematopoietic stem cell transplantation,” said pediatric oncologist Dr. Marie Bleakley, the paper’s senior author, who is a member of Fred Hutch’s Clinical Research Division.

T cells, a linchpin of the immune system, have a variety of molecules on their surface, known as receptors, that recognize cells that are foreign or diseased and kill them. To boost the immune system’s ability to recognize and attack these “invaders,” researchers may transfer genes for a tumor-specific T-cell receptor into the T cells collected from a patient’s transplant donor.

In this work, Bleakley and colleagues exploited a specific “minor histocompatibility antigen,” or minor H antigen, found on the surface of leukemia cells in some patients. Using this group of antigens as targets is being re-examined now that the basic principles of cancer immunotherapy are better understood and potent T-cell immunotherapy is a clinical reality. Because these antigens are expressed predominantly on blood-forming cells, targeting them could provide a potent and selective anti-leukemia treatment with little risk to other cells.

TCR therapy differs from CAR T-cell therapy in that the latter involves creating receptors that are not found in nature. The former occurs naturally in humans, though the receptors we have can vary. While CAR T-cell therapies are known to be effective in treating B-cell acute lymphoblastic leukemia, or ALL, it has not yet been successful in acute myeloid leukemia or T-cell ALL.

Bleakley’s team broke new ground by identifying T-cell receptors that were especially potent in their targeting of a minor H antigen found on the surface of leukemia cells. Using these genetic blueprints, they then were able to extract these receptors from select blood samples provided by donors. Next, they inserted these receptors into T cells from donors for patients who could perhaps benefit from having such “supercharged” T cells to seek and destroy cancer cells with the targeted antigen.

Although no patients have yet received these TCRs, the engineered T cells efficiently and specifically killed target cells in laboratory tests.

“T-cell receptors isolated from minor H antigen-specific T cells represent an untapped resource for developing targeted T-cell immunotherapy to manage leukemia relapse,” Bleakley said, adding that the construct used in this study could serve as a prototype for others targeting similar antigens. Her research team has established a new technique to discover antigens that may be exploited as targets and has identified and characterized five novel minor H antigens.

Bleakley is aiming to launch a Phase 1 clinical trial in December 2017. If results from the lab are borne out in clinical trials, this form of adoptive T-cell therapy could join a growing immune-based arsenal. Fred Hutch researchers and clinicians are pioneers in the development of a variety of T-cell therapies for blood-related and other cancers.

Drug combination may improve impact of immunotherapy in head and neck cancer

Checkpoint inhibitor-based immunotherapy has been shown to be very effective in recurrent and metastatic head and neck cancer but only in a minority of patients. University of California San Diego School of Medicine researchers may have found a way to double down on immunotherapy’s effectiveness.

In a paper published in the journal JCI Insights on September 21, researchers report that a combination of toll-like receptors (TLR) agonists — specialized proteins that initiate immune response to foreign pathogens or, in this case, cancer cells — and other immunotherapies injected directly into a tumor suppresses tumor growth throughout the whole body.

“The mechanism reverses the phenotype of a tumor by changing its inherit properties to make the tumor more immunogenic,” said Ezra E.W. Cohen, MD, professor of medicine at UC San Diego School of Medicine and associate director for translational science at UC San Diego Moores Cancer Center and senior author on the paper. “In this study, the combination of immunotherapy drugs resulted in the complete elimination of cancer cells and even when re-challenged the tumors did not recur.”

Macrophages are specialized immune cells that destroy targeted cells. They are supposed to present antigens to the immune system to get it started, but in cancer they stop doing that so the immune system is unable to recognize the cancer. The combination of drugs restored the ability of macrophages to initiate a tumor response and allow the immune system to eliminate the cancer.

To improve the efficiency of checkpoint inhibitor immunotherapy on human papillomavirus-negative and HPV-positive head and neck cancers, the team of researchers combined synthetic TLR7 and TLR9 that were developed by Dennis Carson, MD, Professor Emeritus at UC San Diego School of Medicine, with an inhibitor of the protein called programmed death-1 receptor (PD-1) which is responsible for turning off T cells.

TLR agonists cause an innate immune response — that is, the rapid response to a foreign substance in the body. This immediate protection comes at a cost since the nonspecific immune response may harm healthy cells if activation of the immune systems persists. PD-1 inhibitors stimulate an adaptive response calling on B cells and T cells to respond to a specific target, but this process takes longer to go into effect.

In mouse models, the combined TLR agonists and PD-1 inhibitors injected directly into a tumor incited a tumor-specific response by T cells which prevented metastasis or the spread of the cancer. When cancer had already spread, the TLR and anti-PD-1 combo eliminated the primary tumor as well as distant tumors. The combination therapy was more effective than either agent alone.

The next step should be to study these drugs in a clinical setting for head and neck cancer using FDA-approved immunotherapy. In addition, Cohen suggests studying these agents with other combinations such as chemotherapy and radiation therapy.

“As we make the tumor more immunogenic we should be making other therapies more effective and eliminate the cancer completely,” said Cohen.

KEYNOTE-040 evaluates pembrolizumab in head and neck cancer

Immunotherapy with the checkpoint inhibitor pembrolizumab may be a better option than standard treatments for patients whose head and neck cancer has spread, or recurred after an initial round of chemotherapy, according to results of the Keynote-040 trial presented at the ESMO 2017 Congress in Madrid. (1)

Although the 19% improvement in overall survival among patients treated with pembrolizumab did not meet the prespecified difference for statistical significance, it was nevertheless a clinically meaningful difference for this population who only lived seven to eight months, on average, after initiating treatment, said lead investigator Dr. Ezra Cohen, from the University of California, San Diego Moores Cancer Center, in La Jolla, California.

“Even though the study did not meet its primary endpoint, I still think it is a positive trial,” he said. “It reinforces that pembrolizumab should continue to be offered as an important option for all patients with this devastating disease.”

The KEYNOTE-040 trial was a global, open-label, phase 3 study which included patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) after a platinum-based chemotherapy.

Patients were randomised to receive either pembrolizumab (n=247) or standard of care (SOC) treatment (n=248), which was the investigator’s choice of either methotrexate, docetaxel, or cetuximab.

Median overall survival (OS) was only marginally higher in the pembrolizumab compared to standard treatment arm (8.4 versus 7.1 months, hazard ratio [HR] 0.81 95% CI 0.66-0.99, P= .0204), however for a subset of patients who had PD-L1-expressing tumours, pembrolizumab was associated with dramatic and significantly improved outcomes.

Specifically, among patients with combined tumour and immune cell PD-L1-expression (CPS) of at least 1%, median OS was 8.7 months with pembrolizumab versus 7.1 months with standard treatments (HR 0.75; 95% CI 0.59-0.95, P=.0078), and among patients with PD-L1-expression in more than 50% of their cancer cells, median OS was 11.6 versus 7.9 months respectively (HR 0.54; 95% CI 0.35-0.82, P=.0017).

Compared to the other treatments, pembrolizumab measured up well in terms of side-effects.

“In almost every category it had a better side-effect profile, meaning a lower incidence of toxicity, versus standard treatments,” said Cohen. “The exception is hypothrodism, which occurred in 13% of those treated with pembro versus only 1% of those given other treatments.”

Overall, Cohen said the KEYNOTE-040 trial reinforces what is already known about anti-PD therapy in head and neck cancer. “From a clinician’s perspective I would feel the same in any country. This is a meaningful therapy that improves survival.”

Asked to comment for ESMO, Dr. Amanda Psyrri, from the University of Athens Medical School, and Attikon University Hospital in Athens said: “Keynote-040 did not reach its primary endpoint of overall survival; however, pembrolizumab was superior to investigator’s choice in terms of toxicity, an important consideration in treatment decisions for these poor-prognosis patients with recurrent/metastatic platinum-refractory HNSCC. As the authors point out, subsequent immunotherapy in the SOC arm may have confounded OS analysis. The magnitude of treatment effect was greater in patients with PD-L1 combined positive score (CPS) ? 1%, especially those with CPS ?50%,suggesting that pembrolizumab may represent the preferable treatment option for this subset of patients.”

Immune cells may be key to better allergy, infection therapies

By learning how a recently discovered immune cell works in the body, researchers hope to one day harness the cells to better treat allergies and infections, according to new Cornell University research.

Type 1 regulatory (Tr1) cells are a type of regulatory immune cell that help suppress immune responses, including inflammation and tissue damage, but very few details were known about their development and function.

A new study with mice and humans, published in the journal Nature Communications, describes how an enzyme called ITK plays a crucial role in the development of Tr1 cells during an immune response. The enzyme offers an entry point for researchers to manipulate the development of Tr1 cells to enhance them to treat allergies, for instance, or block their development to treat viral and bacterial infections.

“The more we understand about how these cells develop, the signals and pathways they use, the more likely we’ll be able to devise approaches to manipulate them,” said Avery August, professor of microbiology and immunology in Cornell’s College of Veterinary Medicine and the paper’s senior author. Weishan Huang, assistant research professor of microbiology and immunology, is lead author.

Doctors employ antigen immunotherapy to treat allergies by administering a regimen that exposes a patient to increasing doses of an allergen over a period of months. Since allergies are caused by an overactive immune response to an allergen, the treatment works because Tr1 cells help suppress the immune system and lower inflammation. In the future, clinicians may want to enhance the pathway to produce more Tr1 cells, August said.

But when treating viral infections such as the flu, bacterial infections and tumors, clinicians may want to selectively block the pathway to lower the number of Tr1 cells. In experiments with mice, August and colleagues found that Tr1 cells increase when a mouse is infected with viruses or bacteria or when fighting tumors. By tempering the development of Tr1 cells, and carefully reducing their activity to suppress the immune response, patients may recover faster from certain diseases.

“This is a balance because these cells are there for a purpose, and we think their purpose is to make sure the immune system doesn’t destroy and cause pathology in an immune response,” August said.

The danger with flu, for example, is that at a certain point other types of immune system T cells, whose purpose is to kill infected cells, start to destroy tissue. In such cases, an overactive immune response can lead to death.

“We’d have to do experiments to find out whether we can tune the function of Tr1 cells,” August said, “so we balance the beneficial aspects of the immune response with the damaging aspects of the immune response.”

In the study, August, Huang and their colleagues bred genetically altered mice so they carried a gene that makes Tr1 cells glow green when they develop, which allows for easy tracking. They then bred another type of mouse that had fluorescent Tr1 cells and also allowed the researchers to specifically block the enzymatic activity of ITK. Using the same protocol, they created a third type of mouse that lacked ITK.

In both the mice where ITK was inhibited and the mice that lacked ITK, Tr1 cells failed to develop. Using blood cells from anonymous human volunteers, they got the same results.

In a second experiment, the researchers identified a second critical enzyme in the pathway that leads to the development of Tr1 cells. This other enzyme, called IRF4, is a transcription factor that regulates the expression of a number of genes and proved key for controlling whether Tr1 cells developed. The team also confirmed that the same pathway exists in people.

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

UH Seidman Cancer Center Expert Presents Novel Triple-Negative Breast Cancer Immunotherapy Trial at 2016 San Antonio Breast Cancer Symposium

Meeting focuses on state-of-the-art breast cancer research, including immunotherapeutic approaches

A researcher from University Hospitals Seidman Cancer Center discussed his upcoming immunotherapy clinical trial for triple-negative breast cancer at the 2016 San Antonio Breast Cancer Symposium. The annual symposium is the premier meeting for more than 7,500 physicians and scientists dedicated to breast cancer treatment, featuring state-of-the-art breast cancer research such as experimental biology, etiology, prevention, diagnosis, and therapy of both breast cancer and premalignant breast disease.

Joseph Baar, MD, PhD, Director of Breast Cancer Research at UH Seidman Cancer Center and Associate Professor at Case Western Reserve University School of Medicine, shared details about a phase II clinical trial testing the effectiveness of combining the chemotherapy drugs carboplatin and nab-paclitaxel with an immunotherapeutic agent called pembrolizumab (Keytruda) for use in patients with metastatic triple-negative breast cancer. Dr. Baar’s poster presentation was part of the Ongoing Trials-Targeted Therapy session on Dec. 8, 2016.

“Up until now, women with triple-negative breast cancer have only had one treatment option, which is chemotherapy. However, more recently, we’ve seen that the immune modulator pembrolizumab improves outcomes in patients with metastatic triple-negative breast cancer,” said Dr. Baar. “As a result, it is now critical to explore how the addition of pembrolizumab to chemotherapy might improve survival in patients with this type of breast cancer.”

Triple-negative breast cancer is a highly aggressive form which comprises 10-15 percent of newly diagnosed early-stage breast cancer. Most triple-negative tumors are high grade and have a high incidence of recurrence and metastases (spreading to other organs). Unlike other types of breast cancer, there is no standard follow-up treatment for triple-negative breast cancer to prevent recurrence.

As triple-negative breast cancer progresses, tumor cells express a protein ligand called PD-L1, which interacts with the PD-1 receptor on T-cells. T-cells are the immune system’s primary mechanism for fighting back against harmful foreign invaders. The PD-L1 to PD-1 interaction prevents the T-cell from responding to the tumor as a threat. Pembrolizumab binds to the T-cell’s PD-1 receptors and therefore blocks the PD-1 to PD-L1 interaction, allowing the T-cells to be activated against the tumor cells. The research team hypothesizes that the addition of such an immunotherapeutic agent to chemotherapy will allow the body’s natural immune response to reduce disease recurrence to a greater extent than either modality alone.

This is the first phase II trial to study the effectiveness of combining these two chemotherapeutic agents with the immunotherapeutic agent pembrolizumab for this type of cancer.

The trial will enroll approximately 30 patients beginning in early 2017. Eligible patients must have radiologically measurable and documented metastatic triple negative breast cancer, be mostly functional day to day as measured by an ECOG performance status of between zero and one, must not have received more than two prior therapies for this disease, and must be willing to undergo a preliminary biopsy for research purposes. The trial is sponsored by Merck, which produces pembrolizumab as Keytruda.

“Trials our faculty members present at SABCS and other research meetings around the world illustrate the remarkable advances in oncology taking place today,” says Neal J. Meropol, MD, Chief, Division of Hematology and Oncology, University Hospitals Seidman Cancer Center and Associate Director for Clinical Research, Case Comprehensive Cancer Center at Case Western Reserve.

The symposium, which began Dec. 6 and continues until Dec. 10, 2016, is hosted by The Cancer Therapy & Research Center at the University of Texas Health Science Center at San Antonio, the American Association for Cancer Research, and Baylor College of Medicine.

Combination Immune Therapy Shows Promise Against Hodgkin Lymphoma

The combination of two new drugs that harness the body’s immune system is safe and effective, destroying most cancer cells in 64 percent of patients with recurrent Hodgkin lymphoma, according to the results of an early-phase study.

Presented Dec. 5 at the annual meeting of the American Society of Hematology in San Diego, the study in 19 patients found that the combination of brentuximab vedotin (marketed as Adcentris) and nivolumab (Opdivo) decreased tumor size or spread (achieved remission) to some degree in all patients after three months of treatment.

Researchers say the dual therapy was “generally well tolerated,” with “manageable” side effects, such as itchiness and rash, and that only two patients who experienced inflammation in the lungs were withdrawn from treatment.

The multicenter clinical trial, led by a researcher at the Perlmutter Cancer Center at NYU Langone Medical Center, was conducted in patients for whom initial chemotherapy or stem cell transplantation had failed to stop cancer cell growth. The research team says its latest results extend work presented at the same meeting in 2015, which found that a similar combination, with brentuximab vedotin and ipilimumab (Yervoy), also was safe and highly active against lymphoma.

“Although our study offers reason for optimism, the results of larger, longer-term studies already underway are needed before combination immunotherapy could become the new standard of care for people whose Hodgkin lymphoma returns after initial treatment,” says study lead investigator and hematologist-oncologist Catherine Diefenbach, MD. The disease, she notes, affects mostly those under age 40, with one in 10 experiencing relapse, leading to some 1,300 deaths per year. Most cases of Hodgkin lymphoma are considered curable if diagnosed and treated early.

“If further testing proves successful, such dual therapies could potentially become an alternative curative regimen for relapsed Hodgkin lymphoma,” says Diefenbach, an assistant professor at NYU Langone and clinical director of lymphoma program services at the Perlmutter Cancer Center.

Diefenbach says the team’s experiments were inspired by her laboratory’s research in 2012, which had found that in patients with Hodgkin lymphoma, the workhorses of the immune system, or circulating T cells, showed signs of immune dysfunction that could make them less likely to be activated.

This led her and her colleagues to test whether drugs that spur the immune system to attack cancer cells, such as “checkpoint inhibitors” like nivolumab and ipilimumab, would work well with targeted chemotherapy with brentuximab vedotin, a drug known as an antibody-drug conjugate.

Like a Trojan horse, researchers say, brentuximab vedotin homes in on CD30, a protein on the surface of some Hodgkin lymphoma cells, and then delivers an attached dose of chemotherapy to destroy the cell. Nivolumab turns off an inhibitory switch, or “checkpoint,” called PD1on T cell surfaces, which is known to prevent the immune system from identifying and attacking tumor cells. (Ipilimumab targets a different checkpoint, called CTLA4.)

Moving forward, Diefenbach says she hopes to apply the concepts from this treatment strategy to other types of non-Hodgkin lymphoma.

Experimental CAR-T Treatment Halted as Two More Patients Die During Clinical Trials

Juno Therapeutics said Wednesday it has suspended a Phase II clinical trial of a cancer drug after two patients suffered cerebral edema earlier this week, leaving one dead and the other not expected to recover. The company’s ‘Rocket’ trial for B cell acute lymphoblastic leukemia is testing a drug it calls JCAR015.

These drugs work by extracting T cells from patients and then equipping them with chimeric antigen receptors, which then zero in on cancer cells. This first generation of CAR-Ts, which is likely to be eclipsed by early-stage efforts, has been known to trigger harsh side effects.

The cause of death in these patients was cerebral edema, or swelling in the brain. Cerebral edema was the same condition that killed three patients earlier this year and forced the company to stop the trial in this summer. Juno, at that time, had blamed the deadly reaction on one of the chemotherapy drugs that it was using to “precondition,” or prepare the patients for JCAR015. The FDA allowed Juno to restart the trial in short order, however, without the chemo drug, called fludarabine.

Juno said it has notified the Food and Drug Administration of the voluntary hold and is working with the agency and the Data and Safety Monitoring Board to determine next steps. Juno’s trials and plans for its other product candidates are not affected, the company said in a prepared statement.

 

T Cell Channel Could Be Targeted to Treat Head and Neck Cancers

 Researchers at the University of Cincinnati (UC) have discovered that an ion channel, active within T cells (white blood cells), could be targeted to reduce the growth of head and neck cancers.

This research, which was reported this month in Cancer Research, shows that defective Kv1.3 channels, which regulate calcium ions (Ca2+) presence in T cells, and Ca2+ abnormalities in tumor infiltrating lymphocytes—cells that attack and kill cancer cells—may contribute to the inability of the immune system to fight off head and neck cancers.

By regulating their expression at the cellular level and using the body’s own immune response to fight the tumor cells, patients with these cancers could have better, more effective outcomes.

“Head and neck squamous cell carcinoma is the sixth most common type of cancer, with a 5-year survival of 50 percent,” says Laura Conforti, PhD, professor in the Department of Internal Medicine at the UC College of Medicine, a researcher within the UC Cancer Institute and corresponding author on the study. “The heterogeneity of these tumors, the complex anatomy of the head and neck region and the proximity of these tumors to several vital organs and structures present a challenge in conventional treatment options of these cancers.

“Immunotherapies aimed to boost the immune system to fight cancer cells are showing promising results in this group of patients.”

Conforti says that to survive and spread, tumors create a cozy microenvironment where they often go unrecognized by the immune system.

“The extent to which CD8+ cells, a type of T cell capable of killing cancer cells, infiltrate the head and neck tumor affects disease progression and responsiveness to therapy,” she says. “Also, how well CD8+ lymphocytes function within the confines of the tumor microenvironment determines their ability to eradicate cancer cells, and in the case of head and neck solid tumors, tumor infiltrating lymphocytes have multiple functional defects, decreasing their ability to work correctly.”

“The function of CD8+ lymphocytes depends on Ca2+, which is controlled by ion channels. In particular, Kv1.3 ion channels regulate Ca2+ influx into T cells. In this study, we assessed the role of Kv1.3 channel and Ca2+ fluxes on these lymphocytes’ function in head and neck cancer,” she adds.

Conforti says that her team, led by Ameet Chimote, PhD, research associate in the Division of Nephrology and Hypertension, used tumor samples and blood from 14 patients with head and neck cancers to analyze how Kv1.3 effected the function of tumor infiltrating T lymphocytes.

They found a 70 percent reduction in functional Kv1.3 channels in tumor infiltrating lymphocytes as compared to the blood T cells, which was accompanied by a decrease in Ca2+ levels and reduced ability to attack and kill cancer cells.

“Overall our data showed that suppression of Kv1.3 channels in these lymphocytes, the cells that fight off cancer, contribute to their decreased function, raising the possibility that this channel may be used as a potential marker of functionally competent T cells that have infiltrated the tumor mass,” Conforti says. “These findings are particularly timely as a recently published study in Nature proposes these channels as potential new target for immunotherapy in cancer. The authors in this study reported that overexpressing these channels in an animal model with cancer lead to increased survival.

“Further studies are needed on this T cell channel to find out more about its effects on head and neck cancer and ways we can target it to improve outcomes.”

JCAR014 Clinical Data Published In Science Translational Medicine: Patients With Advanced Lymphoma In Remission After T-Cell Therapy

In a paper published today in Science Translational Medicine, researchers from Fred Hutchinson Cancer Research Center shared data from an early-phase study of patients with advanced non-Hodgkin lymphoma (NHL) who received JCAR014, a Chimeric Antigen Receptor (CAR) T cell treatment, and chemotherapy. CAR T cells are made from a patient’s own immune cells that are then genetically engineered to better identify and kill cancer cells.

The paper reported the results of the first 32 patients in a dose-finding trial of JCAR014 following a round of chemotherapy, called lymphodepletion, designed to create a more favorable environment for the CAR T cells to grow in the patient’s body. Key findings of the study demonstrated the importance of the choice of lymphodepletion regimen and the effects of different doses of CAR T cells. 50 percent of the 18 patients who were evaluable for efficacy after receiving CAR T cells and chemotherapy agents fludarabine and cyclophosphamide (Cy/Flu) had a complete response, which compares favorably to the 8 percent complete response rate in patients who received JCAR014 plus cyclophosphamide-based chemotherapy without fludarabine. As previously reported, dose-limiting toxicities were observed in some patients in this dose-finding study who received the highest CAR T-cell dose. The study continues with the intermediate CAR T-cell dose.

In patients that received Cy/Flu lymphodepletion and the intermediate dose of JCAR014, the data showed a promising early efficacy and side effect profile. Specifically:

• Overall Response rate: 82 percent (9/11)
• Complete Response rate: 64 percent (7/11)
• Severe Cytokine Release Syndrome: 9 percent (1/11)
• Severe neurotoxicity: 18 percent (2/11)

JCAR014’s hallmark is its use of a one-to-one ratio of helper (CD4+) and killer (CD8+) CAR T cells, which join forces to kill tumor cells that produce CD19, a molecule found on the surface of many blood cancer cells, including lymphoma and leukemia. By controlling the mixture of T cells that patients receive, the researchers can see relationships between cell doses and patient outcomes that were previously elusive. The data also suggest that with a defined one-to-one composition of cells, efficacy of treatment is increased, while toxic side effects are minimized.

“With the defined composition treatment, we are able to get more reproducible data about the effects of the cells – both the beneficial impact against the cancer and any side effects to the patient,” said Fred Hutch clinical researcher Dr. Stan Riddell, one of the senior authors of the paper, along with Dr. David Maloney. “We are then able to adjust the dose to improve what we call the therapeutic index – impact against the tumor, with lower toxicity to the patient.”

“This study shows that at the right dose of CAR T cells and lymphodepletion, we can achieve very good response rates for NHL patients who have no other treatment options,” said Dr. Cameron Turtle, an immunotherapy researcher at Fred Hutch and one of the study leaders.

For Juno Therapeutics (NASDAQ: JUNO), these insights from the JCAR014 study are key to its development of JCAR017, a similar product candidate for the treatment of CD19 positive blood cancers. Like JCAR014, JCAR017 uses a one-to-one ratio of helper and killer CAR T cells, and the company believes it has the potential to be a “best-in-class” treatment for non-Hodgkin lymphoma, chronic lymphocytic leukemia, and adult and pediatric acute lymphoblastic leukemia. JCAR017 is currently in a phase I, multi-center study.

“We are encouraged by the efficacy and duration of response that we are seeing with defined composition CAR T treatment in patients with lymphoma and other B-cell malignancies,” said Mark J. Gilbert, Juno’s Chief Medical Officer. “We hope that the insights from JCAR014 will make it possible to bring more life-saving treatments to more patients with blood cancers.”

In addition to Fred Hutch researchers, the study team also included scientists from Juno and the University of Washington. Juno provided one of the trial’s sources of funding, along with the National Institutes of Health, Washington state’s Life Science Discovery Fund and the Bezos Family Foundation.