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First-In-Human Clinical Trial Aims to Extend Remission for Children and Young Adults With Leukemia Treated With T-Cell Immunotherapy

Phase 1 pilot study utilizes T-cell antigen presenting cells to prolong the persistence of cancer-fighting chimeric antigen receptor (CAR) T cells, reduce the relapse rate

After phase 1 results of Seattle Children’s Pediatric Leukemia Adoptive Therapy (PLAT-02) trial have shown T-cell immunotherapy to be effective in getting  93 percent of patients with relapsed or refractory acute lymphoblastic leukemia (ALL) into complete initial remission, researchers have now opened a first-in-human clinical trial aimed at reducing the rate of relapse after the therapy, which is about 50 percent. The new phase 1 pilot study, PLAT-03, will examine the feasibility and safety of administering a second T-cell product intended to increase the long-term persistence of the patient’s chimeric antigen receptor (CAR) T cells that were reprogrammed to detect and destroy cancer.

The research team, led by Dr. Mike Jensen at the Ben Towne Center for Childhood Cancer Research at Seattle Children’s Research Institute, is exploring this strategy after discovering that of the patients who relapse in the PLAT-02 trial, about half of them have lost their CAR T cells. Lasting persistence of the CAR T cells is critical in combating a recurrence of cancer cells.

“While it’s promising that we’re able to get these patients who are very sick back into remission, we’re also seeing that the loss of the CAR T cells in some patients may be opening the door for the cancer to return,” said Dr. Colleen Annesley, an oncologist at Seattle Children’s and the lead investigator of the PLAT-03 trial. “We’re pleased to now be able to offer patients who have lost or are at risk of losing their cancer-fighting T cells an option that will hopefully lead to them achieving long-term remission.”

In the PLAT-03 trial, patients will receive “booster” infusions of a second T-cell product, called T antigen-presenting cells (T-APCs). The T-APCs have been genetically modified to express the CD19 target for the cancer-fighting CAR T cells to recognize. Patients will receive a full dose of T-APCs every 28 days for at least one and up to six doses. By stimulating the CAR T cells with a steady stream of target cells to attack, researchers hope the CAR T cells will re-activate, helping to ensure their persistence long enough to put patients into long-term remission.

PLAT-03 is now open to patients who first enroll in phase 2 of Seattle Children’s PLAT-02 trial and who are also identified as being at risk for early loss of their reprogrammed CAR T cells, or those who lose their reprogrammed CAR T cells within six months of receiving them.

The PLAT-03 trial is one of several trials that Seattle Children’s researchers are planning to open within the next year aimed at further improving the long-term efficacy of T-cell immunotherapy. In addition to the current T-cell immunotherapy trial that is open for children with neuroblastoma, researchers also hope to expand this promising therapy to other solid tumor cancers.

“We are pleased to be at a pivotal point where we are now looking at several new strategies to further improve CAR T-cell immunotherapy so it remains a long-term defense for all of our patients,” said Dr. Rebecca Gardner, Seattle Children’s oncologist and the lead investigator of the PLAT-02 trial. “We’re also excited to be working to apply this therapy to several other forms of pediatric cancer beyond ALL, with the hope that T-cell immunotherapy becomes a first line of defense, reducing the need for toxic therapies and minimizing the length of treatment to only weeks.”

To read about the experience of one of the patients in the PLAT-02 trial, please visit Seattle Children’s On the Pulse blog.

The T-cell immunotherapy trials at Seattle Children’s are funded in part by Strong Against Cancer, a national philanthropic initiative with worldwide implications for potentially curing childhood cancers. If you are interested in supporting the advancement of immunotherapy and cancer research, please visit Strong Against Cancer’s donation page.

For more information on immunotherapy research trials at Seattle Children’s, please call (206) 987-2106 or email immunotherapy@seattlechildrens.org.

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Nanoparticles Reprogram Immune Cells to Fight Cancer

Researchers at Fred Hutchinson Cancer Research Center have developed biodegradable nanoparticles that can be used to genetically program immune cells to recognize and destroy cancer cells — while the immune cells are still inside the body.

In a proof-of-principle study to be published April 17 in Nature Nanotechnology, the team showed that nanoparticle-programmed immune cells, known as T cells, can rapidly clear or slow the progression of leukemia in a mouse model.

“Our technology is the first that we know of to quickly program tumor-recognizing capabilities into T cells without extracting them for laboratory manipulation,” said Fred Hutch’s Dr. Matthias Stephan, the study’s senior author. “The reprogrammed cells begin to work within 24 to 48 hours and continue to produce these receptors for weeks. This suggests that our technology has the potential to allow the immune system to quickly mount a strong enough response to destroy cancerous cells before the disease becomes fatal.”

Cellular immunotherapies have shown promise in clinical trials, but challenges remain to making them more widely available and to being able to deploy them quickly. At present, it typically takes a couple of weeks to prepare these treatments: the T cells must be removed from the patient and  genetically engineered and grown in special cell processing facilities before they are infused back into the patient. These new nanoparticles could eliminate the need for such expensive and time consuming steps.

Although his T-cell programming method is still several steps away from the clinic, Stephan imagines a future in which nanoparticles transform cell-based immunotherapies — whether for cancer or infectious disease — into an easily administered, off-the-shelf treatment that’s available anywhere.

“I’ve never had cancer, but if I did get a cancer diagnosis I would want to start treatment right away,” Stephan said. “I want to make cellular immunotherapy a treatment option the day of diagnosis and have it able to be done in an outpatient setting near where people live.”

The body as a genetic engineering lab

Stephan created his T-cell homing nanoparticles as a way to bring the power of cellular cancer immunotherapy to more people.

In his method, the laborious, time-consuming T-cell programming steps all take place within the body, creating a potential army of “serial killers” within days.

As reported in the new study, Stephan and his team developed biodegradable nanoparticles that turned T cells into CAR T cells, a particular type of cellular immunotherapy that has delivered promising results against leukemia in clinical trials.

The researchers designed the nanoparticles to carry genes that encode for chimeric antigen receptors, or CARs, that target and eliminate cancer. They also tagged the nanoparticles with molecules that make them stick like burrs to T cells, which engulf the nanoparticles. The cell’s internal traffic system then directs the nanoparticle to the nucleus, and it dissolves.

The study provides proof-of-principle that the nanoparticles can educate the immune system to target cancer cells. Stephan and his team designed the new CAR genes to integrate into chromosomes housed in the nucleus, making it possible for T cells to begin decoding the new genes and producing CARs within just one or two days.

Once the team determined that their CAR-carrying nanoparticles reprogrammed a noticeable percent of T cells, they tested their efficacy. Using a preclinical mouse model of leukemia, Stephan and his colleagues compared their nanoparticle-programming strategy against chemotherapy followed by an infusion of T cells programmed in the lab to express CARs, which mimics current CAR-T-cell therapy.

The nanoparticle-programmed CAR-T cells held their own against the infused CAR-T cells. Treatment with nanoparticles or infused CAR-T cells improved survival 58 days on average, up from a median survival of about two weeks.

The study was funded by Fred Hutch’s Immunotherapy Initiative, the Leukemia & Lymphoma Society, the Phi Beta Psi Sorority, the National Science Foundation and the National Cancer Institute.

Next steps and other applications

Stephan’s nanoparticles still have to clear several hurdles before they get close to human trials. He’s pursuing new strategies to make the gene-delivery-and-expression system safe in people and working with companies that have the capacity to produce clinical-grade nanoparticles. Additionally, Stephan has turned his sights to treating solid tumors and is collaborating to this end with several research groups at Fred Hutch.

And, he said, immunotherapy may be just the beginning. In theory, nanoparticles could be modified to serve the needs of patients whose immune systems need a boost, but who cannot wait for several months for a conventional vaccine to kick in.

“We hope that this can be used for infectious diseases like hepatitis or HIV,” Stephan said.  This method may be a way to “provide patients with receptors they don’t have in their own body,” he explained.  “You just need a tiny number of programmed T cells to protect against a virus.”

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Immunotherapy for Glioblastoma Well Tolerated; Survival Gains Observed

A phase one study of 11 patients with glioblastoma who received injections of an investigational vaccine therapy and an approved chemotherapy showed the combination to be well tolerated while also resulting in unexpectedly significant survival increases, researchers at the Duke Cancer Institute report.

Patients treated with the study drug (dose-intensified temozolomide and vaccines) were continuously monitored for toxicity and adverse events. Study patients experienced known side effects with temozolomide, including nausea, lymphopenia, thrombocytopenia and fatigue.

There were no treatment limiting adverse events and no adverse events related to the cellular portion of the vaccine. One patient developed a grade 3 vaccine-related allergic reaction to the GM-CSF component of the vaccine. The patient was able to continue vaccinations in which the GM-CSF was removed and had no subsequent adverse events.

Although the trial was small and not designed to evaluate efficacy, four of the 11 study patients survived for more than five years following treatment with a combination of vaccine and the drug temozolomide, a first-line chemotherapy drug for glioblastoma. That outcome is uncommon for glioblastoma, a lethal brain cancer that has a median survival of nearly 15 months when treated with the current standard of care.

“This is a small study, but it’s one in a sequence of clinical trials we have conducted to explore the use of an immunotherapy that specifically targets a protein on glioblastoma tumors,” said Duke’s Kristen Batich, M.D., Ph.D., lead author of a study published online April 14 in the journal Clinical Cancer Research. “While not a controlled efficacy study, the survival results were surprising, and they suggest the possibility that combining the vaccine with a more intense regimen of this chemotherapy promotes a strong cooperative benefit.”

Batich and colleagues–including senior author John Sampson, M.D., Ph.D., chair of Duke’s Department of Neurosurgery — treated 11 patients as part of a single arm study to test the safety of using a dose-intensified regimen of temozolomide along with a dendritic cell vaccine therapy that selectively targets a cytomegalovirus (CMV) protein. CMV proteins are abundant in glioblastoma tumors, but are absent in surrounding brain cells.

In earlier clinical trials, the researchers used the dendritic cell vaccine to teach T-cells to attack tumor cells, and their data suggested these vaccines could be enhanced when primed by an immune system booster. A separate clinical trial found that higher-than-standard doses of temozolomide, combined with an immune-stimulating factor, also primed the immune system and enhanced the response of a different vaccine target.

The researchers built on those findings in the current study. They used a combination of the dendritic cell vaccine therapy and the immune-stimulating factor, which was administered as injections following dose-intensified regimens of temozolomide. The 11 patients received at least six vaccine treatments.

“Our strategy was to capitalize on the immune deficiency caused by the temozolomide regimen,” Batich said. “It seems counter-intuitive, but when the patient’s lymphocytes are depleted, it’s actually an optimal time to introduce the vaccine therapy. It basically gives the immune system marching orders to mount resources to attack the tumor.”

Batich said the approach significantly slowed the progression of patients’ tumors. Typically, glioblastoma tumors begin to regrow after standard treatment at a median of eight months, but for study participants, recurrence occurred at a median of 25 months.

“These are surprisingly promising clinical outcomes,” Sampson said. “However, it is important to emphasize that this was a very small study that used historical comparisons rather than randomizing patients to two different treatments, but the findings certainly support further study of this approach in larger, controlled clinical trials.”

The research team has received approval to launch a new study that will compare the standard dose of temozolomide vs. the dose-intensified regimen along with the vaccine in glioblastoma patients.

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Immune Responses Against a Virus-Related Skin Cancer Suggest Ways to Improve Immunotherapy

Researchers at Seattle’s Fred Hutchinson Cancer Research Center and the University of Washington say a new study suggests ways to improve immune therapy for certain cancers including a virus-associated form of Merkel cell carcinoma, a rare, aggressive skin cancer.

Merkel cell carcinoma, or MCC, is 35 times less common than melanoma, but on average, it is about three times more likely to be deadly. There are currently no therapies approved by the Food and Drug Administration for this cancer. About 80 percent of the 2,000 new cases diagnosed in the U.S. each year are caused in part by a virus – Merkel cell polyomavirus – that is often present on normal skin without consequence.

Previous studies have linked a weaker immune system with poorer survival in patients with the disease. In this study, researchers at UW and Fred Hutch, a leading center developing experimental, genetically engineered T-cell therapies, conducted an unprecedented in-depth analysis of the immune system’s “killer” (CD8) T cells that respond to a specific part of the Merkel cell polyomavirus.

The immune system’s effectiveness is determined by many factors, including how well T cells can infiltrate a tumor and bind to the “foreign” proteins, or antigens. More specifically, T cells seek out and attach to antigens using their highly diverse T-cell receptors. In this multicenter study, the researchers focused on T cells that target a piece of the virus referred to as “KLL”.

“We found that a surprisingly low number of patients – only about 20 percent – had T cells specific for the ‘KLL’ region of the virus. This suggests that about 80 percent of patients aren’t making T cells that recognize this very prominent target,” said Dr. Paul Nghiem, affiliate investigator of the Clinical Research Division at Fred Hutch, and professor of medicine, Division of Dermatology at the University of Washington School of Medicine.

Nghiem, senior author of an article published online Jan. 16 in Cancer Immunology Research, said the study is important because an increase in the KLL-specific T cells infiltrating the tumor is associated with a striking improvement in patient survival.

First author Natalie Miller, an MD/PhD student in Nghiem’s research lab, performed in-depth analysis on blood and tumors from 12 patients who had T cells that could recognize KLL.

“T cells that recognize this part of the virus are incredibly diverse. In fact, among these 12 patients, there were 397 unique ways for the T cells to recognize this single short piece of the virus; only one T-cell receptor was shared between two patients,” Miller said. “In addition, T cells from patients with better outcomes tended to stick to the viral target more tightly. This suggests that while nature has created many ways for the immune system to fight this cancer, some ways are better than others. Our hope is that these ‘better’ T-cell receptors can be turned into a therapy for patients who do not have them.”

At diagnosis, virus-associated MCC is typically treated with surgery and radiation, and although 95 percent of patients appear to be cancer-free, the disease returns in about half of cases, Nghiem said. The cancer often responds to chemotherapy, but the response is short-lived, with most tumors progressing about three months after treatment begins.

In April, Nghiem’s group published findings of a phase 2 clinical trial of the immunotherapy drug pembrolizumab, reporting that the “checkpoint inhibitor” helped to revive “exhausted” T cells, providing significant and lasting responses in more than half of patients.

With their new findings, the research team expects to propose the launch of a clinical trial in which T cells engineered with the most effective tumor tracking and attacking receptors would be transferred to patients who are unable to mount an effective immune response of their own.

“Like Merkel cell carcinoma, cancers that have a viral component provide a variety of potential targets for immunotherapy. We’re eager to find out if transgenic T cell therapy can ‘reprogram’ lymphocytes to eliminate tumors in combination with checkpoint inhibition,” Nghiem said.

The study was supported by grants from the National Institutes of Health and other sources including the Adaptive Biotechnologies Young Investigator Award, Kelsey Dickson Team Science Courage Research Team Award, Prostate Cancer Foundation Award, ARCS Fellowship, the David & Rosalind Bloom Endowment for MCC Research, the Michael Piepkorn Endowment Fund, the UW MCC Patient Gift Fund, and the Deutsche Forschungsgemeinschaft (SFB TR36).

Nghiem, corresponding author, is a leading expert on MCC and a pioneer of immunotherapy for the disease. His research has shed light on the importance of the immune response to Merkel cell polyomavirus. A practicing physician, he treats patients with MCC and other skin cancers at Seattle Cancer Care Alliance, Fred Hutch’s clinical care partner. He is a consultant for EMD Serono Inc. and receives funding from Bristol-Myers Squibb to perform biomarker studies in MCC clinical trials.

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New Study Highlights Role for Immune Cells in Cancer’s Ability to Evade Immunotherapy

One of the main reasons cancer remains difficult to treat is that cancer cells have developed a multitude of mechanisms that allow them to evade destruction by the immune system. One of these escape mechanisms involves a type of immune cell called myeloid-derived suppressor cells (MDSCs). A recent study led by Sharon Evans, PhD, Professor of Oncology and Immunology at Roswell Park Cancer Institute, provides new insight into how MDSCs enable tumor cells to circumvent immune attack and offer the potential for improving cancer immunotherapy. The research has been published today in the journal eLife.

Tumor cells cause extensive expansion of MDSCs, which are associated with poor prognosis in patients with various types of cancer. Dr. Evans and colleagues used a state-of-the-art microscopy system to visualize T lymphocytes, the professional killers of cancer cells within the arsenal of the immune system. They discovered that MDSCs can blunt the immune reaction to cancer by preventing the ability of T lymphocytes to enter lymph nodes, important sites where the immune response to invading cancers becomes ramped up. MDSCs accomplish this by removing a molecule known as L-selectin from the surface of T lymphocytes that is essential for cellular trafficking into lymph nodes. As a result, the protective immune response to cancer is severely compromised.

Given the rapid movement of cells within the circulation, one of the most surprising findings of this investigation was that MDSCs can act directly on T cells within fast-flowing blood to limit their widespread trafficking to lymph nodes. This subversive activity of MDSCs was not restricted only to T lymphocytes but included B lymphocytes, which are responsible for generating protective antibodies against tumor cells. The team’s research established for the first time that B lymphocytes are also a target of MDSCs in cancer.

“This investigation could lead to the identification of novel therapeutic targets that bolster the body’s protective mechanisms against the development of metastatic disease,” says Dr. Evans, senior author of the new study. “These new insights may allow us to address a pressing challenge faced by physicians: how to determine which cancer patients are most likely to benefit from T lymphocyte-based immune-therapeutics.”

“Because these immune-suppressive myeloid cells were found to act at long distances to prevent the activation of the T lymphocyte response to tumors, this research reinforces the important message that routine profiling of the cellular constituents within tissues does not always provide the whole picture in cancer,” adds the paper’s first author, Amy Ku, MD/PhD student in the Department of Immunology at Roswell Park.

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New Ovarian Cancer Immunotherapy Study Poses Question: Can Microbiome Influence Treatment Response?

Roswell Park Study with pembrolizumab in untried combination is first ovarian cancer clinical trial to incorporate gut flora analysis

A new clinical study underway at Roswell Park Cancer Institute is the first to test the combination of the immunotherapy pembrolizumab with two other drugs as treatment for recurrent epithelial ovarian cancer, and is also the first ovarian cancer clinical trial to incorporate analysis of patients’ microbiomes — the bacteria present in the human gut and other organs.

This new study, led by Principal Investigator Emese Zsiros, MD, PhD, FACOG, Assistant Professor of Oncology in Roswell Park’s Department of Gynecologic Oncology and Center for Immunotherapy, is a phase II clinical trial that will enroll approximately 40 patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, and will evaluate the impact of the combination of the PD1-targeting antibody pembrolizumab (Keytruda) with intravenous bevacizumab (Avastin) and oral cyclophosphamide (Cytoxan) on antitumor immune responses and on progression-free survival.

Pembrolizumab has been approved by the U.S. Food and Drug Administration for treatment of advanced melanoma, some metastatic non-small cell lung cancers and recurrent squamous cell head/neck carcinoma, but has only been tested in a small number of ovarian cancer patients, as a single drug and showing modest response. The investigators say a strong scientific rationale supports their hypothesis that the combination of pembrolizumab with two other drugs that have already been approved to treat ovarian cancer — bevacizumab and low-dose oral cyclophosphamide — may have much broader benefit for patients.

“Our biggest hope is that by trying these three drugs in combination, we can significantly extend the lives of patients with recurrent ovarian cancer. We also hope to minimize the side effects associated with chemotherapy drugs, and to markedly improve the quality of our patients’ lives,” says Dr. Zsiros. “We will be looking at potential biomarkers that will tell us who can most benefit from this therapy combination and to better understand how cancer cells and immune cells communicate with one another so that we can design better medications to kill cancer efficiently.“

As part of this study, the clinical team will analyze blood, tumor, stool, vaginal and skin microbiome samples, looking to identify possible associations between these markers with clinical outcomes and tumor response. The study, which is supported by a grant from Merck & Co. Inc., maker of pembrolizumab, will be one of the first to analyze these bacteria to determine possible associations with response to immunotherapeutic agents in patients with cancer.

“We’re looking at how to improve our immune defenses to cancer, but we’re looking at it from a variety of angles,” says Dr. Zsiros. “There’s a whole new area of research suggesting that what’s going on in our gut, our gut flora, has a huge influence on your overall health and happiness, and this study will extend that work into some new directions.”

According to the National Cancer Institute, epithelial ovarian cancer is one of the most common gynecologic malignancies, and is the fifth most frequent cause of cancer death in women.

 

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Molecular Switch Controlling Immune Suppression May Help Turn Up Immunotherapies

Researchers at University of California San Diego School of Medicine and Moores Cancer Center have identified a strategy to maximize the effectiveness of anti-cancer immune therapy. The researchers identified a molecular switch that controls immune suppression, opening the possibility to further improving and refining emerging immunotherapies that boost the body’s own abilities to fight diseases ranging from cancer to Alzheimer’s and Crohn’s disease.

The findings are published in the September 19 online issue of Nature.

“Immunotherapies, such as T cell checkpoint inhibitors, are showing great promise in early treatments and trials, but they are not universally effective,” said Judith A. Varner, PhD, professor in the Departments of Pathology and Medicine at UC San Diego School of Medicine. “We have identified a new method to boost the effectiveness of current immune therapy. Our findings also improve our understanding of key mechanisms that control cancer immune suppression and could lead to the development of more effective immunotherapies.”

When confronted by pathogens, injury or disease, the initial response of the body’s immune system comes in the form of macrophages, a type of white blood cell that express pro-inflammatory proteins called cytokines that, in turn, activate T cells, another immune cell, to attack the health threat. The macrophages then switch gears to express other cytokines that dampen T cell activation, stimulating tissue repair.

In chronic inflammatory diseases such as Alzheimer’s and Crohn’s, however, macrophages associated with the malignancy continue to produce pro-inflammatory cytokines and other substances that kill or transform normal cells. In cancer, highly abundant microphages express anti-inflammatory cytokines that induce immune suppression, effectively stopping the healing process.

In the Nature paper, Varner and colleagues pinpoint a key, suspected player: an enzyme in macrophages called PI-3 kinase gamma (PI3Ky). In mouse studies, they found that macrophage PI3Ky signaling promotes immune suppression by inhibiting activation of anti-tumor T cells. Blocking PI3Ky activated the immune response and significantly suppressed growth of implanted tumors in animal models. It also boosted sensitivity of some tumors to existing anti-cancer drugs and synergized with existing immune therapy to eradicate tumors. Varner and her colleagues at the Moores Cancer Center also identified a molecular signature of immune suppression and response in mice and cancer patients that may be used to track the effectiveness of immunotherapy.

“Recently developed cancer immunotherapeutics, including T cell checkpoint inhibitors and vaccines, have shown encouraging results in stimulating the body’s own adaptive immune response,” said co-author Ezra Cohen, MD, who heads the cancer immunotherapy program at Moores Cancer Center. “But they are effective only on a subset of patients, probably because they do not alter the profoundly immunosuppressive microenvironment created by tumor-associated macrophages. Our work offers a strategy to maximize patient responses to immune therapy and to eradicate tumors. ”

The Nature paper builds upon other work by Varner and colleagues. In a paper first published online in May in Cancer Discovery, Varner’s team reported that blocking PI3Ky in tumor-associated macrophages stimulated the immune response and inhibited tumor cell invasion, metastasis and fibrotic scarring caused by pancreatic ductal adenocarcinoma (PDAC) in animal models.

In humans, PDAC is the most common malignancy of the pancreas It’s aggressive and difficult to treat. Though only the 12th most common type of cancer in the United States, pancreatic cancer is the fourth most common cause of cancer-related death.

“PDAC has one of the worst 5-year survival rates of all solid tumors, so new treatment strategies are urgently needed,” said Megan M. Kaneda, PhD, an assistant project scientist in Varner’s lab and collaborator on all of the papers.

In a December 2015 paper published online in Cancer Discovery, Varner and colleagues described animal studies that revealed how disrupting cross-talk between B cells (another type of immune cell) and tumor-associated macrophages inhibited PDAC growth and improved responsiveness to standard-of-care chemotherapy.

Specifically, that research team, which included scientists in San Francisco, Oregon and Switzerland, reported that inhibiting Bruton tyrosine kinase, an enzyme that plays a crucial role in B cell and macrophage functions, restored T cell-dependent anti-tumor immune response. In other words, it reactivated the natural, adaptive immune response in tested mice.

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Q&A with Heat Biologics’ Founder and CEO Jeffrey Wolf on T Cell Stimulating Cancer Immunotherapies

Immuno-oncology, a field of fast advancing science that activates a patient’s own immune system against cancer, holds great promise.  A number of companies in the field are developing treatment platforms, many of which are patient-specific (autologous) and therefore costly. Heat Biologics’ ImPACT (Immune Pan-Antigen Cytotoxic Therapy) is fully allogeneic, off-the-shelf and cost-efficient, offering the potential to enhance patients’ natural immune response against certain cancers.

ImPACT therapy transforms living allogeneic cells into “antigen pumps” that continuously secrete antigens in the patient’s body to robustly stimulate the immune system against the targeted cancer. While ImPACT therapy may be applicable to a wide range of cancers, Heat is currently conducting multiple clinical trials in two indications.

Currently in Phase 2, HS-410 represents the first potential new immunotherapy to treat non-muscle invasive bladder cancer (NMIBC) and is being evaluated as both a monotherapy as well as in combination with standard of care.  Heat’s second product candidate, HS-110, is being evaluated in a Phase 1b trial in combination with nivolumab (Opdivo®), a Bristol-Myers Squibb PD-1 checkpoint inhibitor, for the treatment of non-small cell lung cancer (NSCLC).

Data from its Phase 2 NMIBC trial, as well as data from its NSCLC trial, will be reported in the fourth quarter of this year.

The Bio Connection recently spoke with Heat Biologics’ Founder and CEO Jeffrey Wolf about the Company’s ImPACT immuno-oncology platform.

Q: There is a lot of excitement around the potential for T cell therapies. Can you tell us more about your proprietary ImPACT platform and its advantages compared to others on the market and in development?

Wolf: Our ImPACT platform technology is an off-the-shelf therapeutic anti-cancer vaccine that stimulates a uniquely potent CD8+ T cell response against a broad array of cancer tumor antigens. We feel it potentially provides the broadest and most robust immune system stimulation against targeted cancers, and the intradermal injection has proven to be a very user-friendly route of administration.

Another main advantage really comes with the ease-of-use and cost benefits relative to being allogeneic and not patient-specific.  Autologous or “personalized” therapeutic vaccine approaches require the extraction of blood or tumor tissue from each patient and the creation of an individualized treatment; whereas, our product candidates are fully allogenic, do not require extraction of individual patient materials or custom manufacturing.  As such, our product candidates can be mass-produced and readily available for immediate patient use, offering logistical, manufacturing and other cost benefits compared to one-off, patient-specific approaches.

Using our ImPACT platform technology, we have developed two product candidates and have reported favorable safety profiles to-date, shown clinical evidence of mechanism of action and early signals of efficacy.  Furthermore, we have begun work on our second generation platform technology, ComPACT, which combines a T cell priming vaccine and T cell co-stimulator in a single product, offering the potential benefits of combination immunotherapy in a single drug without the need for multiple independent biologic products.  Again, this is in line with developing ease-of-use and cost efficient therapies.

Q: As an off the shelf product, ImPACT can benefit from scalable low cost manufacturing relative to autologous therapies. Can you tell us how this key competitive advantage can help Heat Biologics both leading up to and following FDA approval?

Wolf: We have already begun planning our commercial production and have found that our platform technology scales well.  By the time we have our Phase 3 trials up and running, we will be in a manufacturing setup that will support commercial launch.  The major competitive advantage is that we can scale the manufacturing and stockpile bulk drug vials for patient use without having to wait for patients.  The off-the-shelf setting is advantageous to us and is well-suited to the workings of established and reputable contract manufacturing partners.

Q: It’s been 25 years since a new treatment was approved for non-muscle invasive bladder cancer.  Given the clear unmet need for a new treatment, can you tell us what size market HS-410 would address, if approved?

Wolf: Bladder cancer is the fifth most common cancer in the United States and represents one of the highest lifetime treatment costs per patient of all cancers.  Most bladder cancer patients – approximately 70 percent – are diagnosed with non-muscle invasive bladder disease, which is the population we are currently targeting.

Q: Approximately half of non-small cell lung cancer patients are not adequately served by drugs on the market today. Can you tell us how HS-110 will serve this unmet need?
Wolf: I believe you are referring to the response rates for the new class of drugs – checkpoint inhibitors – which have been reported to only work on about 30 percent of patients or those patients who have “hot” or inflamed tumors.  By contrast, our trials are indicating that ImPACT therapies are most likely to benefit patients with non-inflamed, or “cold” tumors, by increasing the number of cancer-fighting lymphocytes that infiltrate the tumor and transform them into “hot” tumors.  In fact, we think ImPACT vaccines might be particularly effective when combined with checkpoint inhibitors, which is what our latest trial is designed to show, as we are evaluating HS-110 in combination with nivolumab to treat patients with NSCLC.  We expect to have more data on this by the end of the year.

Q: Since the ImPACT platform can address multiple cancers, which new indications would Heat Biologics pursue next and what size markets those address?

Wolf: We have been focusing our efforts on execution of our current clinical programs, and advancing our next generation platform technology, ComPACT, into the clinic.  We remain excited about the other diseases we may be able to address with these platforms, and are evaluating the best treatment landscape and markets with our physician opinion leaders.  Excitement for our platform technologies continue to build and we are enthusiastic about our products.

For more information on Heat Biologics visit www.heatbio.com (Ticker: HTBX)

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Cancer Research Institute to Honor Three Scientists for Outstanding Contributions to Cancer Immunotherapy Research

The Cancer Research Institute (CRI), a nonprofit organization established in 1953 to advance biomedical research with the goal of developing lifesaving immunotherapies for all forms of cancer, will bestow its highest honors on three scientists who have made fundamental contributions to the fields of immunology and cancer immunology.

CRI will present the 2016 William B. Coley Award for Distinguished Research in Tumor Immunology to Ton N. Schumacher, Ph.D., for his contributions to our understanding of how immune cells identify and target tumor-specific neoantigens, and how this capability can provide anti-tumor immunity. Neoantigens—called so because they are newly formed during cancer development—may represent ideal immunotherapy targets as they are solely expressed on tumor cells. Schumacher was the first to develop a technology for high-throughput analysis of immune cell reactivity to cancer neoantigens, which has allowed researchers to better observe the effects of immunotherapy in patients and has made it possible to develop personalized, patient-specific immunotherapies. With nearly 200 peer-reviewed publications, Schumacher has won numerous awards for his research, including the Meyenburg Cancer Research Award in 2015, Queen Wilhelmina Cancer Research Award in 2014, and the Amsterdam Inventor Award in 2010. He is a senior member of the Department of Immunology of The Netherlands Cancer Institute in Amsterdam, The Netherlands, is a member of the CRI Scientific Advisory Council, and is a CRI-SU2C Cancer Immunology Dream Team grantee.

Receiving the 2016 William B. Coley Award for Distinguished Research in Basic Immunology is Dan R. Littman, M.D., Ph.D., for his definitive work on immune cell differentiation and his contributions to the identification and biology of unique immune cell subsets and their underlying interaction with the microbiome. He discovered the key regulator of Th17 immune cell differentiation, and was the first to identify a bacterial species that induces differentiation of these Th17 cells. A greater understanding of this regulator will allow for the development of novel treatments for cancer as well as inflammatory diseases. Littman is the Helen L. and Martin S. Kimmel Professor of Molecular Immunology, a professor of pathology and microbiology, and a faculty member in the Molecular Pathogenesis program in the Skirball Institute for Biomedical Research at the New York University School of Medicine in New York, NY. He is the recipient of many awards and honors, including the Vilcek Prize in Biomedical Science in 2016 and the New York City Mayor’s Award for Excellence in Science and Technology. Littman is a member of the CRI Scientific Advisory Council and has sponsored 19 CRI postdoctoral fellows since 1990.

CRI will also present the 2016 Frederick W. Alt Award for New Discoveries in Immunology to E. John Wherry, Ph.D. The award honors a former CRI Irvington postdoctoral fellow whose research in academia or industry has had a major impact in the field of immunology. Wherry, who was a CRI Irvington postdoctoral fellow from 2000 to 2003 at Emory University, is currently the professor of microbiology, director of the Institute for Immunology at Perelman School of Medicine, and co-director of the Parker Institute for Cancer Immunotherapy at the University of Pennsylvania, Philadelphia, PA. His discoveries include insights into how changes in gene expression affect T cell exhaustion, a waning of immune function that occurs in response to chronic viral infection and cancer. Current immunotherapies, such as nivolumab (Opdivo®) and pembrolizumab (Keytruda®), work in part by reversing T cell exhaustion. Wherry is on the Thomson/Reuters Highly Cited Researchers list, and was selected as one of America’s Young Innovators by Smithsonian Magazine in 2007.

The Coley Award winners receive a stipend of $5,000 and a gold medallion bearing the likeness of Dr. William B. Coley. In addition, Littman will present the 2016 William B. Coley Lecture on Monday, September 26, 2016, as part of the CRI-CIMT-EATI-AACR Cancer Immunotherapy Conference, which will be held September 25-28, 2016, at the Sheraton Times Square Hotel and New York Hilton Midtown in New York City.

The award ceremony honoring Drs. Littman, Schumacher, and Wherry will take place at the Cancer Research Institute’s 30th Annual Awards Dinner on Tuesday, September 27, 2016, at The Plaza in New York City.