(UroToday.com) As an introduction to this case based session, Dr. VanderWeele laid the groundwork for a discussion primarily around T-cell redirection in advanced prostate cancer to prevent cancer progression and death. This is an interesting and important topic as immunotherapy has not been as effective in prostate cancer as opposed to other solid tumor malignancies. There are putative tumor antigens in prostate cancers that could be exploited for immunotherapy purposes. However, challenges in this field have included the relative immune-excluded microenvironment of prostate cancer, potential unique difficulties in immunotherapy targeting primarily bone metastases, and the comorbidities of this patient population.
After each speaker presented, there was a discussion, the questions and answers of which are included below.
Q for Dr. Narayan: You commented on combination therapy approaches. What agents do you think show the most promise for combinations.
A: Dr. Narayan: We have taken the approach in our first-in-human studies to monitor changes in the tumor microenvironment that may suggest appropriate combinations or adjunctive studies. In our institutional study we saw evidence of up-regulation of immune checkpoints, which suggests that checkpoint inhibitors may be useful. I would caution this is a limited data set so far with only a few patient samples, so we need to build out the data with PSMA CARs and others to learn what the similarities and differences are.
Dr. Schweizer: BiTEs are not as nimble as CAR-T, and so there are already ongoing combination studies such as combining AMG160 with anti-PD-1 agents
Q for Dr. Dorff: Will PSMA PET-CT have any role in following patients treated with PSMA CAR? Is there a role for this imaging for screening?
A: Dr. Dorff: Its very appealing to do PSMA PET scans to select patients with strong PSMA expression, but we do not know how much PSMA expression is required to allow an immunotherapy response. Further work to even define what constitutes response on a PSMA-PET is needed. There is also potential for the development of other PET tracers such as PSCA.
Dr. Narayan: In our study we did serial biopsies and assays PSMA expression by immunohistochemistry. We realized early on that this had limited test characteristics. I think PSMA PET needs to be incorporated at screening and longitudinally in these studies to better understand its potential utility for patient selection in the future.
Q: The tumor microenvironment is dynamic and adapts by becoming immunosuppressive. Could the panel speak to strategies to limit this evolution in response to BiTEs or CAR-T therapies.
A: Dr. Schweizer: The idea is to target other immunosuppressive markers. For example with CAR-T there are strategies which include a dominant negative TGFbeta receptor to limit the immunosuppressive function of that pathway. Another example would be treatment with pembrolizumab, or adding a CD28/PD-L1 switch to make PD-L1 less immunosuppressive.
Dr. Dorff: These post treatment biopsies are so critical to understanding the evolution of immunosuppressive signals in the tumor microenvironment. The Priceman lab at City of Hope has found that cyclophosphamide conditioning seems to be important for modulating the immunosuppressive microenvironment, so we are interested in asking the question of whether repeated dose of CAR-T with a second course of lymphodepletion may lead to better proliferation, persistence, and durable activity.
Q for Dr. Schweizer: Can you say more about the cytokine panel you mentioned and how you use this information.
A: Dr. Schweizer: I am at a center that is very interested in understanding the immunology of these responses, and these panels include many inflammatory cytokines like IL-6 and IL-1. Clinically, we tend to respond more to how the patient is doing from a stability standpoint, though these cytokine levels may add some information about what treatments you might want to use to help the patient or what trajectory the patient is taking.
Q: What are your thoughts on dexamethasone premedication and its possible negative effects on T cell priming and proliferation?
A: Dr. Dorff: We are definitely concerned about this, yet we have seen really profound and some long lasting responses despite dexamethasone premedication. The CRS is really strongest with the first few doses and gets less and less, so we are able to pull off dexamethasone in some cases. At the end of the day our first objective is to keep the patient safe, so we use what we need to get them through the inflammatory syndromes.
Q: At what CRS grade are the trials recommending stopping therapy?
A: Dr. Schweizer: We allow CRS, because if you included something like grade 4 CRS as a dose limiting toxicity, then you would not be able to do these trials. We focus on trying to get the patient through these toxicities without long term, lasting consequences.
Q: I am curious to hear the panels thoughts on any potential NK-cell engagers or CARs.
A: Dr. Narayan: Its an attractive strategy for prostate cancer, though we currently do not have any active NK cell protocols at my institution.
Q: Can you comment on the advantages of these innovative immune approaches compared to other systemic approaches such as radioligand therapy?
A: Dr. Dorff: My goal has been to create a durable remission. The radioligand therapies are very active and promising, but we know that most patients will become resistant within the first year. If we can get these therapies to function more optimally, then we may see that a short course of intensive therapy may result in a more lasting remission. Ultimately, we need to explore all these approaches and it may be that sequences or combinations will end up being optimal.
Dr. Narayan: One challenge we will face with trials in this space is that patients will have been treated with radiopharmaceuticals before enrolling on this trial. It will be important to understand how these therapies change the tumor microenvironment and potential response to T-cell redirecting therapies
Dr. Dorff: To the point of targeting the same antigen, there are other therapeutics in development for other ligands like KLK2 (radiopharmaceutical, CAR, and BiTE).
Q: For other therapies, toxicity can be an indicator of efficacy. Do you think T-cell therapies should be escalated until CRS is present?
A: Dr. Schweizer: It’s a balance, and you don’t want the patient to get too sick. Most patients treated with BiTEs experience CRS that is easier to manage than for CAR-T, but I’m not sure that you want to explicity induce CRS as a marker for efficacy.
Dr. Dorff: We are not 100% sure that you need to have CRS to see if there is disease response.
Dr. Narayan: These are different therapies than conventional cytotoxics, and so its not clear that pushing the therapeutic index until toxicity is really the right approach.
Q: To what extent are the patients that have enrolled on these trials seeking out these therapies versus these therapies being selected more by the patient?
A: Dr Schweizer: Patients know about immunotherapy and there are a lot of potential advantages especially with CAR-T therapies. I get a lot of patients who seek us out for these therapies, and I think the excitement is justified.
Presented by: David James VanderWeele, MD, PhD, Northwestern University
Written by: Alok K. Tewari, MD, PhD, medical oncologist at the Dana-Farber Cancer Institute, @aloktewar on Twitter during the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, Fri, June 3 – Mon, June 7, 2022.
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