Looking Ahead: What’s New In 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?

One of the things that we’ve done with our research over time is reduced the chemotherapy dose. We did this in an effort to reduce toxicity and to make the treatment easier to administer. We have reduced our chemotherapy conditioned regimen down to a very standard dose of cyclophosphamide, 300 mg/m2, for three days plus fludarabine, 30 mg/m2, for three days.

We treated 22 patients, all had advanced lymphoma. Nineteen patients had defuse large B-cell lymphoma. Two patients had follicular lymphoma and one patient had mantle cell lymphoma. The overall response rate was 73 percent with 55 percent complete remissions. Of the complete remissions we had 12 complete remissions. Eleven of those complete remissions are still ongoing at this time. The longest complete remission we have ongoing from that trial is 24 months. So we can see sustained remissions with this treatment.

Also from this trial of low-dose chemotherapy followed by CAR T cells we saw some very interesting immunologic correlates. We found that interleukin-15 (IL-15) levels in the blood were very closely associated with response. Patients who had ended up with higher IL-15 levels in their blood had a much better chance of having a response to the therapy. CAR T cell levels in the blood also were higher in patients who had higher levels of IL-15 which is not too surprising because we know that IL-15 is an important cytokine for promoting the growth and survival of T cells. We were very happy with those results, in particular the fact that the responses were durable.

Can you talk about the expansion of this CAR treatment?

This CAR which is designated at the NCI FMC63-28Z has been commercially taken over and developed by Kite Pharma. Kite has a large multicenter trial that they’re working on that they’ve recruited over 100 patients. So we are very happy to see that our work is being expanded out to a much larger number of patients in multicenter trials at this time.

Are there different concerns you have with a patient who get an autologous and an allogeneic transplant?

It’s a very different patient setting. Patients who have had allogeneic transplants have basically gone through every possible treatment that they could get. They’ve had all the standard therapies. Those have failed. So the patient had to undergo an allogeneic stem cell transplant. Then after that even the patients had progressive malignancy. These patients really have very, very few options.

As most people are aware, one of the standard therapies for progressive B-cell malignancies after allogeneic stem cell transplant is to do a donor lymphocyte infusion. In this treatment lymphocytes are collected from the original transplant donor and then infused into the patient with lymphoma to try to control the lymphoma.

Unfortunately, the donor lymphocyte infusions have inconsistent efficacy and have a lot of side effects. Most importantly graft-versus-host disease (GVHD). About one third of patients after donor lymphocyte infusions get acute GVHD. We decided to enhance donor lymphocyte infusions by genetically engineering the donor lymphocytes to express an anti-CD19 CAR. With the anti-CD19 CAR in the T cells, we felt we could more specifically target the T cells to the malignancy. We found that we had nine out of 20 patients who had an overall response: either partial remission or a complete remission.

We had responses in acute lymphoid leukemia, diffuse large B-cell lymphoma, mantle cell lymphoma and follicular lymphoma. Out of the 20 patients, as I mentioned the overall response was nine out of 20, we have five patients out of that 20 who are in ongoing complete remissions or very good partial remissions that have been ongoing for at least 31 months.

We have patients anywhere from 48 to 31 months in progression-free survival despite the fact that they had a horrible prognosis from having progressive disease after allogeneic stem cell transplant. So we’re very happy with that result but obviously there’s room for improvement where we have 25 percent of the patients having the long-term progression-free survival but the other 75 percent not getting that result.

We have a new version of our allogeneic anti-CD19 CAR trial at the NCI that will be opening up for enrollment in April and we also have ongoing autologous anti-CD19 CAR-T cell studies. Our primary autologous anti-CD19 CAR study is a study of a fully human anti-CD19 CAR. Most anti-CD19 CAR studies to date have used CARs that have a significant amount of mouse protein in them. So our current trial at the NCI is a fully human anti-CD19 CAR.

We treated 12 patients in that study, nine patients have had a response so again it’s another successful study of CAR T cells, confirming our previous results with a different CAR that we can get responses in these patients. Out of the nine responses, four of those have been complete remissions. These results are very early obviously, but we’re just happy to see that our other CAR also works and we’re continuing that and continuing to enroll patients.

Another thing we have in the lymphoma field is a brand new trial of anti CD30 CAR T cells which is another fully human CAR. This trial just opened up so for patients that have CD19 negative lymphoma that is expressing CD30 which is often Hodgkin’s lymphoma or T-cell lymphomas we have a trial for them now too.

Is there a space for multiple myeloma in CAR T-cell therapies?

At the NCI, we have two CAR-T cell trials for multiple myeloma. This is a newer area that we’re getting into. We have CAR-T cells that target a protein called BCMA which is, “B-cell maturation antigen.” There is a trial that is a dose escalation. When we’ve reached the highest dose level of the trial we’ve had very good success with this trial as far as getting responses. We have six out of seven patients on the highest dose level who had a response. These responses are much earlier than our CD19 works that’s much less well developed.

So far patients have had good responses. Many have been sustained but some of them are not sustained. Our longest sustained progression-free survival so far has been 66 weeks. We have right now three out of the seven patients who have ongoing progression-free survivals right now. Toxicities are similar to our anti CD19 work with fever, tachycardia, low blood pressure and patients going to the ICU at times. Again it’s a very experimental treatment. It’s very early and it is a dangerous treatment but it certainly has evidence of its efficacy and we’re very excited about improving this treatment also.

Is there a possibility of this therapy expanding to the realm of solid tumors?

It’s possible. I don’t really work in solid tumors and I think solid tumors are going to be a lot harder to treat than hematologic malignancies just because finding good antigens to target is difficult for everything but I think it’s harder for solid tumors and hematologic malignancies. For CAR T cells the antigen that is targeted has to be expressed only on the malignant cells and not on the normal essential organs of the body because the CAR T cells will destroy whatever the antigen has expressed on so I think the key for solid tumors will be finding antigens that are not expressed on essential normal tissues.
 
 
 
 

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