Every day, organ transplant patients around the world take a drug called rapamycin to keep their immune systems from rejecting their new kidneys and hearts. New research suggests that the same drug could help brain tumor patients by boosting the effect of new immune-based therapies.

In experiments in animals, researchers from the University of Michigan Medical School showed that adding rapamycin to an immunotherapy approach strengthened the immune response against brain tumor cells.

What’s more, the drug also increased the immune system’s “memory” cells so that they could attack the tumor if it ever reared its head again. The mice and rats in the study that received rapamycin lived longer than those that didn’t.

Now, the U-M team plans to add rapamycin to clinical gene therapy and immunotherapy trials to improve the treatment of brain tumors. They currently have a trial under way at the U-M Health System which tests a two-part gene therapy approach in patients with brain tumors called gliomas in an effort to get the immune system to attack the tumor. In future clinical trials, adding rapamycin could increase the therapeutic response.

The new findings, published online in the journal Molecular Cancer Therapeutics, show that combining rapamycin with a gene therapy approach enhanced the animals’ ability to summon immune cells called CD8+ T cells to kill tumor cells directly. Due to this cytotoxic effect, the tumors shrank and the animals lived longer.

But the addition of rapamycin to immunotherapy even for a short while also allowed the rodents to develop tumor-specific memory CD8+ T cells that remember the specific “signature” of the glioma tumor cells and attacked them swiftly when a tumor was introduced into the brain again.

“We had some indication that rapamycin would enhance the cytotoxic T cell effect, from previous experiments in both animals and humans showing that the drug produced modest effects by itself,” says Maria Castro, Ph.D., senior author of the new paper. Past clinical trials of rapamycin in brain tumors have failed.

“But in combination with immunotherapy, it became a dramatic effect, and enhanced the efficacy of memory T cells too. This highlights the versatility of the immunotherapy approach to glioma.” Castro is the R.C. Schneider Collegiate Professor of neurosurgery and a professor of cell and developmental biology at U-M.

Rapamycin is an FDA-approved drug that produces few side effects in transplant patients and others who take it to modify their immune response. So in the future, Castro and her colleagues plan to propose new clinical trials that will add rapamycin to immune gene therapy trials like those already ongoing at UMHS.

She notes that other researchers currently studying immunotherapies for glioma and other brain tumors should also consider doing the same. “This could be a universal mechanism for enhancing efficacy of immunotherapies in glioma,” she says.

Rapamycin inhibits a specific molecule in cells, called mTOR. As part of the research, Castro and her colleagues determined that brain tumor cells use the mTOR pathway to hamper the immune response of patients.

This allows the tumor to trick the immune system, so it can continue growing without alerting the body’s T cells that a foreign entity is present. Inhibiting mTOR with rapamycin, then, uncloaks the cells and makes them vulnerable to attack.

Castro notes that if the drug proves useful in human patients, it could also be used for long-term prevention of recurrence in patients who have had the bulk of their tumor removed. “This tumor always comes back,” she says.

The paper’s co-first authors are Yohei Mineharu, M.D., Ph.D., and Neha Kamran, Ph.D. Mineharu is a former member of Castro’s team who is now on the faculty at Japan’s Institute of Biomedical Research and Innovation; Kamran is a postdoctoral research fellow in Neurosurgery. U-M neurosurgery professor and Castro’s longtime collaborator Pedro Lowenstein, M.D., Ph.D. is a co-author, and leads the current clinical trial.

The research was funded by the National Institute of Neurological Diseases and Stroke (NS052465, NS074387, NS057711, NS054193, NS061107, NS082311) as well as by National Institutes of Health training grants TR000433, CA009676 and NS007222; The Phase One Foundation and the U-M Department of Neurosurgery.

Two recently published studies by a research team at University Hospitals (UH) Case Medical Center Seidman Cancer Center have the potential to advance treatments for small cell lung cell cancer (SCLC). This aggressive form of lung cancer has seen no treatment advances in 30 years and “is a disease in urgent need of new drug therapies,” write the study’s authors.

“In small cell lung cancer, which impacts about 30-40,000 people each year in the United States, there has been no therapeutic progress and very little research,” says Afshin Dowlati, MD, lead author and Director of the Center for Cancer Drug Development at UH Seidman Cancer Center. “Additionally, there are no approved targeted therapies for the disease. These studies lay the foundation for future research aimed at finding important new treatments for this highly malignant cancer.”

A study titled, RET Mutation and Expression in Small Cell Lung Cancer, was published in the September issue of Journal of Thoracic Oncology and found a new mutation in SCLC which may play a role in the disease’s development. The researchers found that the genetic mutation, called RET (rearranged during transfection), was linked to rapid cell growth.

The research team examined specimens in its database of metastatic SCLC tumors, one of the largest databases of its kind in the country. They found that the RET mutant protein was potentially linked to faster-growing cells that were sensitive to ponatinib and vandetanib, two new targeted drug therapies. Future clinical trials for patients with the RET mutation are planned to further validate the data.

“We were encouraged to find that these two cancer-fighting therapies are potentially effective at stopping cancer cell growth in certain small cell lung cancers,” says Dr. Dowlati, who is Professor of Medicine – Hematology/Oncology, Case Western Reserve University School of Medicine and a member of the Case Comprehensive Cancer Center. “These findings have the potential to give cancer physicians a new tool to more effectively tailor treatments for patients.”

The other study, published in PLOS One, outlines a novel approach to identify new drug therapies for SCLC based on tumors’ genomic profiles. The research team discovered new molecular targets for treating the disease by extracting data from SCLC tumors to examine drug sensitivity. Through this analysis, they outlined a promising new approach to predict which cancer-fighting drugs would be the most broadly effective at slowing tumor growth.

“This study enabled us to identify which drugs may be the most useful in which types of tumors,” says Dr. Dowlati. “Small cell lung cancer is one of the fastest growing cancers and these studies have yielded small but important therapeutic insights into this disease.” Dr. Dowlati is additionally the Rosalie and Morton A. Cohen Chair in Oncology and the Lucile and Robert H. Gries Endowed Director, Center for Cancer Drug Development at UH Seidman Cancer Center.

Both studies were funded by the UH Seidman Cancer Center, part of the Case Comprehensive Cancer Center at Case Western Reserve.

Pfizer Inc. (NYSE:PFE) and Kyowa Hakko Kirin (Tokyo:4151), have entered into an agreement to explore the therapeutic potential of the combination of Pfizer’s PF-05082566, an investigational, fully humanized monoclonal antibody (mAb) that stimulates signaling through 4-1BB (CD-137), a protein involved in regulation of immune cell activation, proliferation and survival, with Kyowa Hakko Kirin’s anti-CCR4 antibody mogamulizumab, which suppresses some of the immune cells that shield the tumor from the immune system, in a Phase Ib clinical study evaluating the safety and tolerability of the combination in patients with solid tumors.

Under the terms of the agreement, Pfizer and Kyowa Hakko Kirin will co-fund the clinical study, which will be conducted by Pfizer. This study is expected to establish a recommended dose regimen and assess the safety and preliminary efficacy of the combination. This study is expected to begin in 2015 and the results will determine the future clinical development of the combination.

“We believe that combination therapy in immuno-oncology holds great promise to improve outcomes for patients with cancer and provides an exciting opportunity for Pfizer to maximize the potential of our emerging immuno-oncology portfolio,” said Dr. Mace Rothenberg, senior vice president of Clinical Development and Medical Affairs and chief medical officer for Pfizer Oncology. “Our collaboration with Kyowa Hakko Kirin provides an additional important partnership opportunity to explore the potential of 4-1BB as part of a novel immunotherapy combination regimen.”

“With recent progress in the field of cancer immunotherapy, the combination therapy of mogamulizumab and Pfizer’s 4-1BB agonist has the potential to bring significant benefits to patients,” said Yoichi Sato, managing executive officer, vice president, Head of Research and Development Division of Kyowa Hakko Kirin. “Collaborating with Pfizer, a world’s leading pharmaceutical company, on a clinical study in emerging immuno-oncology field is an important component of Kyowa Hakko Kirin’s ongoing transformation into a global specialty pharmaceutical company. We are excited about this opportunity.”

About PF-05082566
PF-05082566 is an investigational, fully humanized mAb that targets 4-1BB (CD-137), a protein expressed in many immune cells. In pre-clinical models, it has shown anti-tumor activity by enhancing T-cell mediated immune responses. Pfizer is currently evaluating PF-05082566 in a Phase I study as a single agent in multiple tumor types, as well as in several combination studies, including a clinical study of PF-05082566 in combination with rituximab in non-Hodgkin lymphoma patients. PF-05082566 is not approved for any indications in any markets.

About Mogamulizumab
Mogamulizumab is a novel, humanized mAb directed against CC chemokine receptor 4 (CCR4). Engineered by Kyowa Hakko Kirin’s unique POTELLIGENT® Technology, the antibody is designed to kill its target cells through potent antibody-dependent cellular cytotoxicity. Mogamulizumab was launched in Japan in May 2012 for the treatment of patients with relapsed or refractory CCR4-positive adult T-cell leukemia-lymphoma (ATL). The drug was approved for indication expansion and was granted marketing authorization in Japan for the treatment of patients with relapsed or refractory CCR4-positive, peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL) in March 2014. Clinical trials with mogamulizumab in ATL, PTCL, and CTCL are ongoing in the US, EU and other countries.

About Pfizer Oncology
Pfizer Oncology is committed to the discovery, investigation and development of innovative treatment options to improve the outlook for cancer patients worldwide. Our strong pipeline of biologics and small molecules, one of the most robust in the industry, is studied with precise focus on identifying and translating the best scientific breakthroughs into clinical application for patients across a wide range of cancers. By working collaboratively with academic institutions, individual researchers, cooperative research groups, governments, and licensing partners, Pfizer Oncology strives to cure or control cancer with breakthrough medicines, to deliver the right drug for each patient at the right time.

Pfizer Inc.: Working together for a healthier world®
At Pfizer, we apply science and our global resources to bring therapies to people that extend and significantly improve their lives. We strive to set the standard for quality, safety and value in the discovery, development and manufacture of health care products. Our global portfolio includes medicines and vaccines as well as many of the world’s best-known consumer health care products. Every day, Pfizer colleagues work across developed and emerging markets to advance wellness, prevention, treatments and cures that challenge the most feared diseases of our time. Consistent with our responsibility as one of the world’s premier innovative biopharmaceutical companies, we collaborate with health care providers, governments and local communities to support and expand access to reliable, affordable health care around the world. For more than 150 years, Pfizer has worked to make a difference for all who rely on us.

About Kyowa Hakko Kirin
Kyowa Hakko Kirin is a leading biopharmaceutical company in Japan focusing on its core business area of oncology, nephrology and immunology/allergy. Kyowa Hakko Kirin leverages antibody-related leading-edge technologies to discover and develop innovative new drugs aiming to become a global specialty pharmaceutical company which contributes to the health and well-being of people around the world.