Looking Ahead: What's New In CAR T-Cell Therapy for Hematologic Malignancies

Jim Kochenderfer, M.D., lends insight to the future of CAR T-cell therapy for hematologic malignancies.
For patients with hematologic malignancies, promise lies in the immunotherapy technique of adoptive cell transfer (ACT). The building blocks of this therapy are T cells which are collected and then altered to produce chimeric antigen receptors or CARs. These CAR T cells are then infused into the patient to multiply, recognize cancer cells and kill those cancer cells that harbor the antigen.

In an interview with CURE, Jim Kochenderfer, M.D. and investigator from the National Cancer Institute in Bethesda, discussed anti-CD19 CAR-T cell gene therapy, results from recent trials and the potential for this therapy, including fully human anti-CD19 CAR T cells and the possibility of its effect in multiple myeloma or solid tumors.

Can you tell us about anti-CD19 CAR T cells?

Anti-CD19 CAR-T cells are a gene therapy approach to treating lymphoma and leukemia that started several years ago now. At the National Cancer Institute (NCI) we opened our first trial in 2009. Since that time we and other groups have continued to develop anti-CD19 CAR T cells as therapy for a variety of B-cell malignancies.

The main thrust of our research is using the patient’s own T cells as a treatment for lymphoma. Since 2009, we’ve treated at the NCI, on our first protocol, 43 patients with lymphoma and chronic lymphocytic leukemia. The general process we use is to have the patient come in and get an apheresis which gives us the peripheral blood mononuclear cells to take to the lab and then genetically engineer those cells to express an anti-CD19 chimeric antigen receptor (CAR). After the cells are collected, the patient comes in and gets some chemotherapy. The chemotherapy is given to enhance the activity of the CAR T cells.

Many investigators have found in mouse models and fairly strong evidence in humans that giving chemotherapy before these CAR T cells enhances the activity of the CAR T cells and increases the chances of remissions. Shortly after that they get their infusion of CAR T cells. After the infusion we require the patients to stay in the hospital for several days at the National Institutes of Health (NIH). It can be anywhere from eight days to 10 days in the hospital. It could be even longer if the patients have toxicity.

What are some of the toxicities seen from this treatment?

There’s a syndrome called cytokine release syndrome which is caused by cytokines being released from the T cells when they contact the lymphoma or leukemia and this causes most prominently fever, tachycardia and hypotension. It can also cause things like abnormalities of blood coagulation, abnormalities in liver tests and renal insufficiency, among other things. There are many other rarer toxicities that we see but those are the main cytokine release toxicities that we see.

Another prominent toxicity that we’ve had to deal with is neurologic toxicity. We have patients who develop things like aphasia, ataxia, confusion; some patients even have gone into comas. So all this toxicity is certainly a major effort with our future researchers to try and reduce that. But it is certainly something we have to let everybody know about - that it is a high risk treatment. It’s not completely safe, it is very experimental and all of our results are very early.

What are some developments and advancements that researchers have enacted?

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