CAR T-Cell Therapy: Where Do We Stand in 2019?

Thomas Kipps, MD, PhD, University of California, San Diego, gives an update on the development of CAR T-cell therapy at the 2019 Lymphoma & Myeloma Congress.

Transcript

I'm at the Lymphoma and Myeloma Congress. I was asked to comment on where we stand with the development of CAR-T-cell therapy, which is the use of chimeric antigen receptors that are transduced into T-cells to allow them to become armed and ready to go against tumor cells in patients with cancer.

There's been tremendous developments in this area. We know now that patients with intractable leukemias or lymphoma can actually have really outstanding complete responses with CAR-T-cell therapy.

What we've seen though is that CAR-T-cell therapy, which initially started with patients who had chronic lymphocytic leukemia, has really been cutting its teeth on patients with acute lymphoblastic leukemia or patients with diffuse large cell lymphoma.

There we have now 2 approved products that target a protein called CD19, which is a differentiation marker that discriminates between B-cells and other cells of the body and allows the T-cells to go after cells which express this protein.

Some of the patients actually who have had very poor disease and have had difficulty with either chemotherapy or newer targeted therapies have achieved complete remissions which allowed them to be approved by the FDA.

What I covered here in the lecture was the differences between what has been approved in terms of the products, and we have various differences that may give them nuanced behavior, or differences in how they work or how effective they may be.

Part of the problem that I mentioned here is the difficulty we have in comparing one product with the next, because the therapy, which is a one-time infusion of your own T-cells that are modified to express the CAR receptor, is usually a one-shot deal where you don't have the ability to have retreatment with a different product.

I think that there's been a very striking lack of comparative clinical trials where patients who are randomized receive one CAR T-cell product versus another. In the absence of that, it's very difficult to try and parse out which therapy is better, or which one is the best.

Now we have had advances in CAR T-cell therapy for patients with chronic lymphocytic leukemia. It's been slower in coming, in particular, because of the advent of small molecule-targeted therapy where we've had tremendous advances in the treatment of patients with chronic lymphocytic leukemia.

There's not been a compelling need to rush into things such as CAR T-cell therapy in that there are other avenues of treatment that might be able to do the job.

However, even with targeted therapies, we're seeing that some patients may prove either intolerant or refractory to these newer agents, such as ibrutinib, or the newer drug, venetoclax, which are quite effective in either having long progression-free survival or in complete responses for many patients.

They don't satisfy the need for all patients, including patients who develop, what we all worry about, Richter's transformation. Clearly, there are patients who are not addressed by these therapies.

As more and more patients are being treated with these therapies and as we see a larger number of patients surviving with therapy, we expect that patients who need something other than what can be provided by the current small molecule inhibitors to require other forms of treatment.

Recently, there's been some very exciting news in terms of how to develop these CAR T-cells in patients with CLL. We're seeing improvements in response rates, notably, in the co-administration of CAR-T-cells with one of these small molecule inhibitors, ibrutinib, has resulted in higher response rates than had been seen in previous trials.

It remains to be seen whether the ibrutinib is clearly required for the increased response. I'm hopeful that we'll be able to have comparative clinical trials which allow us to address this question.

But in the absence of that, clearly, it's important to note that patients with truly intractable disease, who have complex cytogenetics, who have deletion of 17p or p53 mutation or have resistance to ibrutinib or venetoclax therapy can achieve complete remissions without detectable minimal residual disease. And that's really quite as good as it gets.

For those patients fortunate enough to achieve that, we may see a long progression-free survival in the absence of any type of additional therapy. That's really a home run.

We're hoping that more and more patients will achieve this. With some of the more recent trials, we're seeing that about half or more of patients who are treated with the CAR T-cell therapy may achieve this.

What we're trying to grapple with now is where does this all fit in. CAR-T-cell therapy, with new small molecule inhibitors that target enzymes such as BTK, or PI3-kinase, or inhibitors of BCL2, clearly, the problem that we have now is the wealth of riches that we have with new therapies that are really challenging how patients can deal with their treatment and improve their overall survival and outlook.

How do we fit CAR-T-cell therapy into the mix? I think it's quite exciting that we have all these opportunities. With time, we'll be able to sort out what would be the most appropriate time and the appropriate patient to receive CAR T-cell therapy.