Researchers at Mount Sinai School of Medicine are reporting that that it may be possible to use immunotransplants to enhance the efficacy of checkpoint blockade immunotherapy for treating disease-resistant lymphomas. The team has developed a way to use immunotherapy drugs against treatment-resistant non-Hodgkin's lymphomas for the first time by combining them with stem cell transplantation.
Checkpoint blockade therapy is effective in several tumor types. However, it generally is ineffective in non-Hodgkin's lymphomas. It may be time to rethink that now, according to new findings published in the journal Cancer Discovery. The Mount Sinai researchers found that when this immunotherapy is combined with a stem cell transplant (immunotransplant) the process ramps up the T cells to increase the cancer-killing immune response tenfold, allowing it to be effective for non-Hodgkin's lymphoma.
The newest study findings have prompted the initiation of a clinical trial using this immunotransplant approach for treating patients with aggressive non-Hodgkin's lymphoma, which began enrolling patients in May. Study investigator Joshua Brody, MD, director of the Lymphoma Immunotherapy Program at The Tisch Cancer Institute at Mount Sinai, New York, NY, says using immunotransplants to enhance the efficacy of checkpoint blockade therapy could be broadly significant as these immunotherapies are standard therapies for melanoma, kidney cancer, lung cancer, and other tumor types.
Even in settings in which checkpoint blockade therapy proves ineffective, the new data suggest that its efficacy may be “rescued” by an immunotransplant. Brody says the new findings also suggest that the addition of checkpoint blockade may improve other T cell therapies, such as CAR-T therapy. Investigators base these claims on their observation of how the immune system responded to bone marrow transplants, T cell therapy, immunotherapy, and immunotransplant in patients and mouse models.
“We think the approach is extremely promising. Multiple tumor types in the lab models that did not respond to anti-PD1/CTLA4 at all, experienced either significantly prolonged survival or a significant increase in cure rate by using anti-PD1/CTLA4,” says Brody.
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He says there is currently a profound unmet medical need in this patient population. “Most patients with lung cancer, melanoma, and chemo-refractory aggressive lymphomas die from their disease. Current treatment options include other types of chemotherapy or in the case of lymphoma, allogeneic stem cell transplant, which is rarely used in these patients due to poor efficacy and tolerability,” says Brody.
Asked if we are just in the first inning of the ballgame when it comes to this combination approach for treating chemo-refractory aggressive lymphomas, Brody says he is more optimistic than that. “Ballgame is a suboptimal analogy, it implies an unclear outcome at the end. I would say we are finishing the first mile of a marathon. If we keep going, we will win,” says Brody.
Amanda Cashen, MD, associate professor of medicine in the Division of Leukemia and Stem Cell Transplantation at Washington University School of Medicine, St. Louis, Missouri, says this approach has the potential to augment the anti-tumor activity that can been seen with cellular therapy or checkpoint blockade separately. “However, enhancing the anti-tumor activity is likely to also increase immune-mediated toxicities, like cytokine release syndrome and inflammation of various organs. This study is an area of promise, but clinical trials will be needed to understand the balance of efficacy and toxicity,” says Cashen.
She does not envision chemotherapy being replaced anytime soon for treating hematologic malignancies because chemotherapy is effective for many patients. In addition, the costs and toxicity of cellular therapies, including stem cell transplant, remain significant.
“In the big picture, this approach is one of several combination approaches under study. Checkpoint blockade may be helpful in other cellular therapy settings, including after CAR-T treatment. Also, many new CAR-T approaches are in development, which may be effective without the need for checkpoint blockade. I don’t think we’ll be eliminating chemotherapy in the near-term in the hematologic malignancies,” says Cashen.