Metabolic inhibitor IACS-6274 shows early antitumor effects in underserved patients with advanced cancers
The glutaminase inhibitor IACS-6274, discovered and developed within Therapeutics Discovery, appears to be well-tolerated with successful target inhibition and early signs of anti-tumor activity in a biomarker-driven Phase I trial.
The University of Texas MD Anderson Cancer Center and Refuge Biotechnologies, Inc. today announced a strategic collaboration to advance new cell therapies for potential treatment of solid tumors. The agreement pairs Refuge’s innovative technologies with the experience and industrial capabilities of MD Anderson’s Biologics Development platform, within the Therapeutics Discovery division.
Under the agreement, MD Anderson will possess exclusive rights to apply Refuge’s proprietary platform for next-generation cell engineering to its tumor infiltrating lymphocyte (TIL) programs. MD Anderson also will co-develop Refuge’s RB-340, a HER-2 targeted CAR T cell therapy with context dependent inducible down-regulation of PD-1, including Investigational New Drug (IND) filing, Good Manufacturing Practice (GMP) production and Phase I/II clinical trials.
“MD Anderson has extensive expertise in developing and manufacturing innovative cell therapies, including groundbreaking work with TILs,” said Bing Wang, Ph.D., chief executive officer and co-founder of Refuge Biotechnologies. “We look forward to working closely with MD Anderson researchers to apply our technology to this promising field of research, while also advancing development of our lead intelligent cell therapy program.”
Using Refuge’s platform for programming cells to selectively react to tumor cells through direct modulation of gene expression utilizing CRISPR interference and activation, RB-340 is designed to conditionally and smartly down-regulate expression of PD-1 on approaching tumor cells, reducing T cell exhaustion and increasing T cell persistence and proliferation, thus creating better efficacy against solid tumors. Treatment with RB-340 in preclinical models has shown a clear survival benefit compared to conventional CAR T cell therapy. IND filing is anticipated in the first half of 2022, with clinical development of RB-340 focused in solid tumors.
Through its Biologics Development platform, MD Anderson is advancing research into therapeutic applications for TILs – naturally occurring lymphocytes that can recognize cancer cells and penetrate a tumor. MD Anderson and Refuge will explore the use of Refuge’s platform to engineer TILs for enhanced anti-tumor activity.
“It is my belief that TILs are poised for a significant impact in the field of cancer therapy, and engineering improved TILs is a vital part of advancing this modality,” said Jason Bock, Ph.D., vice president of Therapeutics Discovery and head of Biologics Development at MD Anderson. “We have been encouraged by the data coming from Refuge’s applications of its next generation, context dependent and inducible cell engineering platform, and we look forward to incorporating its potential into our TIL programs.”
MD Anderson’s Biologics Development platform is built around an experienced team focused on pioneering impactful biologic therapeutics, including antibodies and cell therapies. With a state-of-the-art GMP cell therapy manufacturing facility, the platform unites MD Anderson research with industrial therapeutic development.
Adoptive cellular therapy is a form of immunotherapy that uses cells from our immune systems, such as T cells, as a treatment for cancer. The immune cells are usually isolated from a patient, expanded and, in some cases, engineered to enhance their natural abilities to eliminate cancer.
This field has grown significantly in recent years with the FDA approval of chimeric antigen receptor (CAR) T cell therapies for certain patients with blood cancers. CAR T cells are engineered to recognize specific targets on cancer cells.
Tumor-infiltrating lymphocytes (TILs) are an experimental cell therapy being developed for treating solid tumors. To learn more about TIL therapy and MD Anderson’s research, we spoke with Jason Bock, Ph.D., vice president of Therapeutics Discovery and head of Biologics Development.
What is a tumor-infiltrating lymphocyte?
Lymphocytes, or white blood cells, are an important part of the immune system that helps the body fight off infections or eliminate diseased cells. Lymphocytes, made up of T cells and B cells, are constantly patrolling the body to identify cells that shouldn’t be present, including cancer.
As cancers grow, lymphocytes recognize these cells as abnormal and penetrate into the tumor. These are the tumor-infiltrating lymphocytes, or TILs.
Once in the tumor, the TILs begin working to kill cancer cells. Sometimes, they’re prevented from doing that by brakes in the immune system or signals from the tumor that weaken the immune response. Immune checkpoint inhibitors were developed to block some of those brakes and unleash the immune cells to attack cancer.
We also can use the TILs themselves, with some improvements, as a form of cell therapy.
How can these cells be used for cancer therapy?
Because TILs come directly from the tumor, they already recognize many targets on the cancer cells. This makes them a very attractive therapy because we don’t have to do anything to point them toward the tumor.
That’s different from CAR T cells, for example, which must be genetically engineered to recognize one, or maybe two, targets. A group of TILs taken from a patient’s tumor may recognize many unique targets. This offers a real therapeutic advantage because it prevents the tumor from evading our efforts by hiding one target at a time.
To use TILs as a therapy, we must help them overcome the hurdles in the tumor environment and effectively eliminate the cancer. We can do this in two ways:
- expanding the TILs
- engineering them with certain attributes
By expanding the TILs, we can give the patient a much larger army of immune cells that is already trained to recognize and attack that patient’s specific tumor.
Engineering TILs enhances their ability to fight the cancer cells. There are several research projects in this area ongoing at MD Anderson. For example, we can genetically engineer TILs to be resistant to signals coming from the tumor that normally turn off the T cells .
What’s the treatment process for patients who undergo TIL therapy?
Currently, TIL therapies are only available through clinical trials. For patients who enroll in a TIL clinical trial, the process begins with a tumor biopsy. That biopsy is then taken to a clinical laboratory, such as our Cell Therapy Manufacturing Facility, to isolate the TILs.
Trained experts perform the expansion and engineering in a process that typically takes about a month. We’re working to improve our speed in this area, though, to get therapy to patients more rapidly.
From there, the process is similar to other cell therapy procedures. When the TILs are ready, we give the patient a short-term chemotherapy regimen to prepare the body for the cells. Then, the patient receives the TILs through infusion, just like a typical blood infusion. Once infused, the TILs travel directly to the tumor to begin their work.
Afterward, the patient receives some immune-modulating therapies, such as interleukin 2 (IL-2), to stimulate the TIL activity. A patient will be in the hospital for at least a few days so doctors can monitor for any side effects or reactions to the therapy. TIL therapy is a one-time treatment.
Are there expected side effects to TIL therapy?
So far, we have not seen any major side effects from the TILs themselves. Most side effects we see come from the chemotherapy regimen or the IL-2, which can be managed.
We are working to engineer TILs that could produce their own immune-stimulatory signal. This would eliminate the need for us to treat the patients with IL-2 and could reduce side effects overall.
Has TIL therapy been successful in treating cancer?
We have been evaluating TIL therapies in clinical studies for years and there are encouraging results in early-phase studies. Most of the studies thus far have treated patients with melanoma, but other indications are now being explored.
What is interesting is that TILs appear to be a long-lasting therapy. We’ve seen evidence that TILs can be found still patrolling the body several years after infusions, and they can eliminate recurrences before we’ve even detected them on scans. Some patients can be tumor-free for many years after a single TIL infusion.
While that is early data, we’re working very hard to understand how that happens so we can maximize benefits for all patients. We’re also working to improve the manufacturing process, which has been a hurdle in the field. Combining MD Anderson’s expertise in TIL therapies with the robust manufacturing capabilities of our cell therapy manufacturing facility, we are hopeful that we can overcome this challenge in the near future.
Why are you excited about the future of TIL therapy?
I believe that TIL therapy offers a promising option for patients with solid tumors. So far, we haven’t seen great success from CAR T or other cell therapies in treating patients with solid tumors. However, by the very nature of TILs, we have years of data demonstrating them to be more successful for these cancer types.
There is a TIL therapy that has completed clinical trials and may be evaluated this year by the Food and Drug Administration, so I am excited to see if perhaps there will be an approved TIL therapy on the horizon.
The great Wayne Gretzky liked to say, “Skate to where the puck will be, not where it is.” I believe TIL therapy is where the puck is going – it is poised for a significant impact in the field of cell therapy. We are proud to be part of bringing those advances to our patients.
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The University of Texas MD Anderson Cancer Center and the Broad Institute of MIT and Harvard today announced the launch of a new translational research platform to study rare cancers and develop a first-of-its-kind resource for the scientific community. The joint initiative will create a catalog of rare cancer models and provide a data resource to accelerate the identification of therapeutics to treat patients diagnosed with rare tumor types.
The National Cancer Institute defines a rare cancer as one with fewer than 40,000 new cases per year. Cumulatively, rare cancers account for roughly one-quarter of all cancer cases and cancer deaths, but the low incidence of each different type of rare tumor presents a significant challenge to efforts to identify effective therapeutic approaches.
“Through this initiative, we hope to overcome some of the challenges that have prevented effective translational research in rare cancers,” said Timothy Heffernan, Ph.D., head of oncology research in MD Anderson’s Therapeutics Discovery division. “By collaborating with the Broad Institute, we have a tremendous opportunity to create a valuable resource for the entire scientific community that will inspire and catalyze a wave of innovative research to advance impactful new therapies to patients in need.”
MD Anderson is the world leader in the diagnosis and treatment of rare cancers; more than 5,000 patients with the rarest diagnoses seek treatment annually. In 2019, MD Anderson established the Rare Tumor Initiative, a multidisciplinary effort to comprehensively characterize rare tumors throughout the course of each patients’ care. This new joint translational research platform builds upon MD Anderson’s existing commitment to rare cancers with the goal of enabling rapid translation of new therapeutic insights.
This collaborative effort between MD Anderson and Broad will generate models of rare tumors from MD Anderson patients at the Broad’s Cancer Cell Line Factory, which works to expand the number and variety (in terms of tumor types and cancer genotypes) of cancer models available for research. These models will be analyzed extensively by the Broad’s Cancer Dependency Map project, an effort to systematically detect genetic and pharmacologic vulnerabilities in cancer in order to identify molecular signatures that could inform novel therapeutic approaches.
"Treatments for rare cancers have lagged behind common tumors in large part because we as a community lack the tools to study and understand their unique biology in the laboratory," explained William Sellers, M.D., director of the Broad's Cancer Program. "This initiative represents a significant opportunity to close that gap and to start identifying new treatment options for patients with rare cancers. We are thrilled to be able to work closely with our colleagues at MD Anderson towards that goal."
The initiative aims to generate more than 100 rare cancer models, and to make those models and associated molecular data available to all members of the cancer research community.
“At MD Anderson, our singular mission is to end cancer,” said Giulio Draetta, M.D., Ph.D., chief scientific officer at MD Anderson. “This collaboration is an excellent example of our focus on meeting the needs of all of our patients through innovative research approaches and is directly aligned with the themes of our institutional strategy. We are excited to have this opportunity to leverage the exceptional science and expertise at the Broad Institute to accelerate new treatments for patients.”
The University of Texas MD Anderson Cancer Center and Boehringer Ingelheim today announced the extension and expansion of their joint Virtual Research and Development Center (VRDC) to explore new molecules from Boehringer Ingelheim’s KRAS (Kirsten rat sarcoma) and TRAILR2 (TNF-related apoptosis-inducing ligand receptor 2) portfolios for the potential treatment of lung cancer, particularly non-small cell lung cancer.
The collaboration, launched in 2019, has successfully combined MD Anderson’s innovative clinical research infrastructure and the patient-driven drug development capabilities of the Therapeutics Discovery division with Boehringer Ingelheim’s pipeline of innovative cancer medicines and expertise in advancing breakthrough therapies. Under the new agreement, joint research will continue for five additional years.
“Our collaboration with MD Anderson strengthens our determination to find solutions for the most difficult-to-treat cancers, and this latest commitment marks an important step forward, especially in our holistic KRAS program,” said Norbert Kraut, Ph.D., head of Global Cancer Research at Boehringer Ingelheim. “We are delighted to extend our collaboration with MD Anderson. With our shared dedication to patients and like-minded approach to innovation, we have the potential to bring the medicines to lung and gastrointestinal cancer patients that they so much need.”
The flexible nature of the VRDC agreement allows the teams to expand their lung cancer indication programs targeting KRAS and TRAILR2, including Boehringer Ingelheim’s first-in-class SOS1::pan-KRAS inhibitor (BI 1701963), inhibitors of KRAS G12C (BI 1823911) and MEK (BI 3011441), as well as a novel undisclosed bi-specific TRAILR2 agonist.
The collaboration already has resulted in a number of joint publications, conference presentations (including at the 2021 AACR Annual Meeting) and clinical trial activities. Boehringer Ingelheim is pursuing a comprehensive mutant KRAS-directed effort with multiple programs expected to enter the VRDC with MD Anderson.
“We are proud to expand our work with Boehringer Ingelheim in a very exciting drug-development space – advancing novel targeted therapies against KRAS and TRAILR2,” said Timothy Heffernan, Ph.D., head of oncology research in Therapeutics Discovery at MD Anderson. “Our collaboration is built upon a strong working relationship and complementary expertise, highlighting how an academic center and a pharmaceutical company can strategically work together to advance innovative therapies for patients with cancer.”
MD Anderson’s Therapeutics Discovery division is anchored by an experienced team of drug development experts working to advance the next generation of cancer therapies. The Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) platform, led by Heffernan, performs cutting-edge translational research to rapidly advance new therapies to the patients most likely to benefit.
KRAS is the most frequently mutated cancer-causing oncogene. One in seven of all human metastatic cancers expresses KRAS mutations, with mutation rates of more than 30 percent in lung adenocarcinomas, more than 40 percent in colorectal cancers and more than 90 percent in pancreatic cancers. No approved treatments for KRAS-driven cancers exist currently, further underscoring the need for continued investment in research and development. Tumor cell-selective activation of TRAILR2 can trigger cancer cell death in indications of high medical need, including lung and gastrointestinal malignancies.
MD Anderson has an institutional financial conflict of interest with Boehringer Ingelheim related to this research and has therefore implemented an Institutional Conflict of Interest Management and Monitoring Plan.