CAR-T Therapy

Dr Miklos provides an overview of chimeric antigen receptor T (CAR-T) cell therapy.


Kami Maddocks, MD: Five years ago, we’d be having very different conversations from the ones we’re able to have today. Our field has advanced in a number of ways in the last 4 to 5 years. Probably what started this, or the biggest initial advance, was the chimeric antigen receptor [CAR] T-cell products approved after 2 or more prior lines of therapy. We’ll discuss those data and the data presented at ASH [American Society of Hematology Annual Meeting] on earlier therapy. But first we’re going to give Dr Miklos his time to shine and tell us a little about what CAR T-cell therapy is, how it works, and the process to get this into patients.

David Miklos, MD, PhD: We’re having this discussion in an hour and a half, and we’re supposed to have this conversation with our patients in less than 60 minutes repeatedly and frequently in different languages. Let me take a shot at how I sell CARs. The goal for many decades has been to take the power of immunotherapy and put it to work in the treatment of cancer. Now that we’ve lived through COVID-19 for 2 years, we’ve become experts—our patients as well—in developing immune responses. We recognize the challenges of having small peptides presented in an HLA [human leukocyte antigen] context recognized by a small subset of a large repertoire of T and B cells.

This is conceptual, but this is your Carl Sagan moment. There are billions of different T cells, but you get only a few winners, and immunology is all about the winners. We have tried to vaccinate against lymphoma and other blood cancers without much success. So finally, as I tell my patients, we hijacked their immune system. We’ve taken and enslaved their T cells irrespective of what they were designed to see, whether that was a vaccine, chickenpox, or hair dander. We’ve done this by inserting a new novel protein with a gene into their chromosomes of the lymphocytes—only the lymphocytes—in a very safe manner in a laboratory where all safety is maintained. Then that modified, supercharged cell—that cell with new capabilities—is brought back to the patients and infused, and it rapidly expands. But we prepared them by decreasing the number of endogenous lymphocytes with the regimen of cyclophosphamide fludarabine that does lymphodepletion.

When we infuse those cells, they expand, doubling every 7 hours. By day 7 or 14, depending on the costimulatory domain, you’re going to have upward of 3 to 4 logs more. Infrequently, we see 50% of the circulating lymphocytes expressing this novel protein that we call a chimeric antigen receptor, or CAR. This CAR is driven like Pac-Man by the recognition of the antigen specific for the cancer. Never before have we had such an important conversation about antigen. How much antigen do you have? Which antigen do you have? What’s the density of that antigen? Did you lose that antigen? That’s going to be a new part of our parlance in discussing treating patients. Did you do the right test and determine how much of the antigen is there, whether we do CAR, T-cell engagers, or antibodies? We’re going to have a whole new discussion about antigen density and how you tested it.

But that immune cell is a lymphocyte. It goes to lymph nodes, and our disease of lymphoma is the popular site for that assassin to go to. Pac-Man likes to go to lymph nodes driven by the antigen, expanding exponentially and killing for weeks and months. In fact, it persists even after the cancer is gone, providing surveillance and some persistence.

What did we accomplish? [There were] 4 things that we all set out to do from the beginning. No. 1, provide a living therapy that expands to meet the need of the patient, able to create more killing for the larger amount of disease, less for the less, and somehow trying to control the toxicity. No. 2, it localizes to where the cancer is. It doesn’t cause off-site toxicity. In a perfect world, it wouldn’t cause your hair to fall out or you to have toxicity, nausea, or CNS [central nervous system] disease. No. 3, it uses cytotoxic killing, something that evolution has perfected through 10,000 generations. Every organism from the sea sponge to humans have this adaptive immune response. And No. 4, it creates persistence, a surveillance system. This is amazing. It’s not surprising that we’d all bet that Steven Rosenberg and Carl June will someday get the Nobel Prize. I hope they do it soon for what has been a landmark paradigm-shifting therapy that has been so efficacious.

Earlier, we talked about the SCHOLAR trial. We all remember when we looked back at 1000 patients and refined it to about 600 and said, “What happened to the patient in 2015 who had unresponsive chemotherapy after 2 lines of therapy or were induction failures to the up-front treatment?” and, “Their median survival is dismal, at 5 to 6 months, and their 1-year overall survival was 12%.” Here’s the good news. I’m sure all of us are looking at much better outcomes for our patients who are now our friends doing follow-up for years to come.

It’s not unreasonable to consider the original clinical trial presented in 2016 in the late-breaking ASH abstract, the ZUMA-1 study that has a 5-year progression-free survival of 37% and an overall survival of 42.6%. That’s 42.6%, and we were talking about 12% at a year. In our experiences going on to other therapies, we’ve been able to improve on that to the point where I expect this to be a 75% or better 1-year survival by the therapies available today. That’s dramatic. Before I go on to talk about the individual agents, I want to applaud what the ability to harness the immune system has done incrementally, beginning with antibody targeting. You couldn’t have done CAR without binding, moving on to the harnessing of the T cells itself.

Transcript edited for clarity.

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