Accelerating Stanford’s Innovative Discoveries in 2023 and Beyond
The 5M Campaign Development of Novel Immunotherapy for T-cell lymphomas
A cornerstone of our translational program is the development of a novel strategy for immunotherapy of T-cell lymphomas. There exists only one potential cure for cutaneous T-cell lymphomas and relapsed systemic T-cell lymphomas: allogeneic bone marrow transplant. But that treatment comes at great risk. It involves swapping the immune system of a patient with that of a matched donor. Not only can this therapy leave a patient vulnerable to infection, it can also lead to a potentially life-threatening complication of graft-versus-host disease, a condition where the donor cells mistakenly start to attack the patient’s normal cells instead of their cancer cells. Because of the risks involved with bone marrow transplant, most patients with T-cell lymphoma will never undergo the procedure.
Our research points to a new alternative approach. Instead of transferring all immune cells from a donor, we may be able to select out immune cells that can kill the lymphoma, and leave the other potentially harmful immune cells behind. The key to this lies in understanding how the immune system is able to distinguish a lymphoma cell from a normal cell.
Over the last several years, we have accumulated evidence that one molecule on the surface of lymphoma cells may be critical in marking it for destruction by the immune system. This immune target, called the T-cell receptor (TCR), is universally present on every lymphoma cell, and universally absent on every normal cell. We believe that we can select donor immune cells targeting the lymphoma TCR, and perhaps even better, we may be able to retrain a patient’s own immune system to recognize the lymphoma TCR as an enemy marker to be destroyed.
There is one key challenge to this strategy. The lymphoma TCR is different for every person. Therefore, we cannot simply create a drug targeting the TCR and give it to all patients. Instead, we have to design the therapy specifically for each patient. This level of customization has dissuaded many potential pharmaceutical partners from joining us in developing this strategy. Nevertheless, recent advancements are bringing us ever closer to the first trial of this novel immunotherapy. mRNA vaccines, such as those used to great effect in addressing the COVID-19 pandemic, are far easier to customize than prior forms of therapy.
As our initial trial, we are planning to test our concept of targeting the lymphoma TCR as part of our allogeneic stem cell transplantation process. In this strategy, we will pool and expand large number of T-cells from HLA-matched donor, boost them with patient-specific TCR, and then select for the activated/boosted, anti-TCR T-cells before infusing them to the CTCL patient. This process will be done in a closed system (Miltenyi Prodigy), thus avoiding additional steps or complications. Compared to the conventional non-boosted, non-selected transplant, we hope to greatly enhance the lymphoma attacking activity without introducing the risk of graft versus host disease.
Our ongoing collaborations with both industry partners as well as interdisciplinary academic faculty at Stanford are aimed at bringing these treatments to the clinic. Current work is being directed towards supporting FDA investigational new drug applications. We are steadily approaching our first clinical trial of TCR therapy, and necessary confirmatory pre-clinical is currently in progress to help make the leap from laboratory experiment to clinical treatment.
The Stanford MCTLP faculty leaders are excited with our progress in the laboratory and are eager to move our novel TCR-based immunotherapy concepts closer to our patients. We are also looking forward to continued development of other novel targeted or combination immune therapies. In conjunction with our evolving research in decoding the molecular mechanisms down to the single cell level and improving our ability to personalize therapies with tailored biomarkers, 2023 and beyond will be years filled with new discoveries that will advance science and therapeutics in CTCL. With the support of donors energized to meet the 5M challenge in our fundraising campaign, we are anticipating an accelerated pace of research to meet our goals.
Learn more about our discoveries of new molecular and immune alterations as well as its development of groundbreaking therapies in an ongoing Zoom series: