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Therapeutics Discovery
The Therapeutics Discovery division at MD Anderson was created to eliminate the bottlenecks that hamper traditional drug development.
Our team of more than 100 dedicated cancer researchers, doctors, drug developers and scientific experts develops small molecule drugs, biologics and cellular therapies, inspired by the needs of MD Anderson cancer patients and guided by the expertise of the center’s clinicians. To create life-saving transformational medicines quickly, safely and effectively, Therapeutics Discovery works with unparalleled proximity to patients and an unmatched wealth of clinical experience.
Therapeutics Discovery doesn’t bring the “bench to bedside” – it starts with the bench at the bedside – with each patient and their cancer.
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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 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.
Disclosures
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.
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