Improving CAR T-Cell efficacy with combinatorial strategies
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In this installment of In Practice, Stephen J. Forman, MD, director of the T Cell Therapeutics Research Laboratory in the Cellular Immunotherapy Center at City of Hope Comprehensive Cancer Center, discusses how a combination of treatment strategies can help improve the overall effectiveness of chimeric antigen receptor T-cell therapies.
As Forman noted, experience in combining other classes of anticancer therapeutics and evaluating their timing has led to more effective treatments. The hope is that a similar strategy for CAR T-cell therapy can improve response rates and durability in hematologic malignancies and solid tumors.
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Q: After you and your patient decide that CAR T-cell therapy is the treatment of choice, how do you prepare the patient for the next steps?
Patients generally undergo a variety of pretreatment tests to assess their organ function — including heart, lungs, liver and kidneys — and a neurological examination, very similar to what is done in the transplant setting. There is also staging of the disease, with scans or bone marrow biopsy depending upon the diagnosis. We then have an information and counseling session with the patient and their family to review the process and potential side effects. Most patients will receive a lymphodepleting chemotherapy regimen before the CAR T-cell infusion, the most common being the combination of fludarabine and cyclophosphamide. This is done for numerous reasons, including recruitment of endogenous cytokines and the creation of ‘space’ in the immune system. Lymphodepletion likely also affects the tumor microenvironment in a way that makes it more hospitable to incoming CAR T cells.
Q: Are there combinatorial strategies available to augment the efficacy of CAR T cells?
As is evident from the clinical trials, not all patients respond to CAR T-cell therapy or if they do, the response may not be durable. Many ways are being explored to improve CAR T-cell efficacy in hematologic malignancies and solid tumors. They include identification of additional target antigens, giving CAR T cells in sequential infusions, or developing dual targeting from a single CAR T cell to recognize two separate antigens and minimize the likelihood of antigen escape.
In addition, given the harsh inhibitory environment of the tumor, strategies are being developed to modify that environment to give CAR T cells a better chance of being efficacious. One obvious way that is being explored is by combining anti-PD-1 or anti-PD-L1 antibody therapy with CAR T cells so the tumor has less opportunity to prevent the T cells from mediating their antitumor activity.
Q: What is the rationale for attempting a combinatorial strategy?
To increase the chances that the CAR T cells can kill the tumor completely and not be inhibited by the tumor microenvironment, which is generally unhospitable to the immune system itself and the CAR T cells.
Q: Are these combinatorial strategies investigational at this point and available only as a part of clinical trials?
At the present time, combinatorial approaches are in clinical trials to make sure that the combinations are safe and effective, because each has its own side effects.
Q: Could CAR-T be more effective for patients with advanced cancers if given as an earlier line of treatment?
We have been asking how early it is reasonable and safe to introduce CAR T cells into the therapeutic approach to patients with cancer, including older patients. Most studies have focused on patients with advanced disease who have failed a number of other therapies. We are hopeful that these approaches will find their way into the initial therapeutics of both hematologic cancers and solid tumors. We have seen this with immunecytokine therapy (bispecific T-cell engagers) and checkpoint inhibitors, which have migrated from being used for end-stage disease to first-line therapy in diseases like melanoma and lung cancer.
Q: Are there any decision-making algorithms that your or your institution follow during the CAR-T process?
Except for patients undergoing treatment with commercial products, everyone at City of Hope is participating in clinical trials, including those for glioblastoma, acute lymphoblastic leukemia, acute myeloid leukemia, myeloma, breast cancer and prostate cancer, with more trials to come. Therefore, trial eligibility determines the decision-making to some degree. For commercial products, there is a CAR T-cell committee that oversees the care of patients in the program. It reviews each patient who has been recommended to receive a commercial CAR-T product to make sure it is the right therapy for the patient and the right time.
Q: Do you consult any professional guidelines during the consultation and decision-making process?
The guidelines in the field are evolving, but CAR T-cell therapeutics — particularly in ALL and lymphoma — have now made their way into the National Comprehensive Cancer Network guidelines, with myeloma soon to come.
Q: Are there red flags that clinicians should be aware of when attempting a combinatorial approach?
A combinatorial approach needs to be done in the context of a clinical trial that is usually overseen by physicians who are already trained in CAR T-cell therapeutics and who often also have a transplant background.
Q: Is there anything else you want other clinicians to know about combinatorial strategies to augment the efficacy of CAR T cells?
My sense is that the research that is ongoing, both preclinically and clinically, will help determine when a combinatorial approach is appropriate and likely will differ among tumor types. The tumor microenvironment and how it varies among different various cancers may also contribute to the effectiveness of combinatorial approaches.
- For more information:
- Stephen J. Forman, MD, can be reached at 1500 E. Duarte Road, Duarte, CA 91010; email: sforman@coh.org.
Disclosures: Forman reports lab support from and a consultant role with Mustang Bio.
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