Modified donor T cells may decrease risk for GVHD

Preclinical studies in mouse models showed that genetically modified donor T cells with a chimeric antigen receptor that recognizes CD19 (CD19-CAR) may have anti-tumor activity in recipients of an allogeneic hematopoietic stem cell transplant without developing graft-versus-host disease (GVHD).

Marcel van den Brink, MD, PhD, head of the division of hematologic oncology, and co-director of the Parker Institute for Cancer Immunotherapy at Memorial Sloan Kettering Cancer Center, and colleagues took T lymphocytes from a bone marrow donor and modified it with a CD19-CAR. The modified cells could eliminate CD19-expressing lymphoma cells but did not cause GVHD.

Marcel van den Brink

HemOnc Today spoke with van den Brink about how additional research can build upon these early findings and potentially improve the efficacy of bone marrow transplantation for patients with CD19–positive hematologic malignancies.

Question : How significant of a challenge is the development of GVHD in patients after transplant?

Answer: GVHD is one of the most serious complications of an allogeneic bone marrow transplantation. It happens in about half of all patients who undergo an allogeneic bone marrow transplantation. In terms of mortality, the 1-year mortality is about 15% or so annually in most countries. So, it is a very serious problem.

Q: What is the need for effective therapies in this area?

A: In terms of therapies to prevent acute GVHD, not much has changed. There are two strategies that are being applied. One is prophylaxis with immunosuppressive drugs such as cyclosporine, tacrolimus, mycophenolate mofetil, rapamycin and a few others. In addition, we can use chemotherapeutic agents, such as methotrexate and cyclophosphamide.

However these strategies have only limited success because still about half or so of our patients will get some form of GVHD. Once a patient develops GVHD the options are even more limited

Corticosteroids are the only proven therapy and if patients fail this, then there are only experimental therapies. Within our field, there are many studies considering what could be a second line of treatment for acute GVHD.

The other form of GVHD is chronic, but our study did not evaluate this type.

Q: How might T cells modified with CAR s reduce the incidence of GVHD?

A: The main goal of genetically engineered CAR T cells is to produce a potent cancer immunotherapy .However T cells are the main culprits of GVHD. So, making a T cell a better killer could result in more and worse GVHD, because these cells will be more revved up to kill.

What was surprising in our study is that this did not happen. We know that about 5% or so of all T cells can recognize antigen found on the tissue of someone else, so called alloantigens. When we engineer donor T cells with CARs then we create T cells that can recognize antigens in two ways: the B cell antigen CD19 through their CAR and another antigen through their endogenous T cell receptor (TCR). If the TCR recognizes an alloantigen then these CAR T cells could cause GVHD.. However, what we found with these T cells could be described as “systems overload”. If a T cell recognizes the alloantigen through the T-cell receptor and CD19 through the CAR, it gets overstimulated and leads to activation-induced cell death or exhaustion. We saw evidence of both, but no matter what the end outcome was, those alloreactive CAR T cells were not functional. They were either killed or paralyzed.

Q: What are the clinical implications this approach could have in the future?

A: They suggest that when a person relapses after bone marrow transplant, infusions with donor T cells modified with CARs might be safer than we expected.

Q: What are your next steps for research?

A: At our center, we are currently planning a clinical trial in patients undergoing an allogeneic bone marrow transplant for a CD19+ malignancy in which we generate donor CD19-CAR T cells and infuse these cells one month after the transplantation to reduce the risk of relapse..

We expect to see little or no GVHD. In this way we hope to optimize the graft-versus-tumor aspect of our bone marrow transplant without causing GVHD.

This trial has gone through most of the committees at our center already, so we hope to open it within the next few months. Meanwhile, in our lab we are trying to work on even better CARs and more sophisticated CARs using different concepts of how we can use CARs also to block T cells that might give you GVHD — called an inhibitory CAR — which is the opposite of activating the T cells. We are doing a lot of that work in mouse models to further optimize CAR therapy after bone marrow transplantation. – by Melinda Stevens

For more information:

Marcel van den Brink, MD, PhD, can be reached at Memorial Sloan Kettering Cancer Research Center, 1250 First Avenue, New York, NY 10065; email: m-van-den-brink@ski.mskcc.org.

Disclosure: van den Brink reports no relevant financial disclosures.