Rosenberg Sees New Milestone in Latest CAR Findings

Steven A. Rosenberg, MD, PhD

A recent study involving a chimeric antigen receptor (CAR) therapy represents a new milestone in the development of this emerging class of immunotherapies because it marks the first time that the approach has demonstrated efficacy in patients with aggressive B-cell malignancies, according to a leading investigator.

In an interview with OncLive, Steven A. Rosenberg, MD, PhD, chief of Surgery at the National Cancer Institute (NCI), discussed the implications of responses to KTE-C19, particularly among patients with chemotherapy-refractory diffuse large B-cell lymphomas (DLBCLs), which his group reported in the Journal of Clinical Oncology.¹

Overall, 15 patients with indolent B-cell malignancies and DLBCLs were enrolled in the phase I/IIA study, with 13 patients evaluable for response. The objective response rate was 92%: eight patients achieved complete remissions (CRs), four experienced partial remissions (PRs), and one had stable lymphoma. One patient died suddenly of unknown causes 16 days after infusion and another patient could not be evaluated because of noncompliance.

Notably, four of seven evaluable patients with chemotherapy-refractory DLBCL achieved CR, including three individuals with ongoing response durations ranging from 9 to 22 months at the time that results were announced in late August.

KTE-C19 is a fusion protein manufactured through the genetic modification of autologous whole peripheral-blood mononuclear cells into T cells that kill CD19-positive cells, which make an attractive target for anticancer therapy since they are expressed only on normal B-cells and on most B-cell malignancies.

In the study, participants received a conditioning regimen of cyclophosphamide (60 or 120 mg/kg) and fludarabine (25 mg/m²), followed by a single infusion of KTE-C19. The dose of the CAR therapy was reduced from 5 x 10⁶ to 1 x 10⁶ CAR-positive T cells/kg during the study to avoid toxicities.

KTE-C19 is among several adoptive cell therapies that have been generating excitement in recent years. The NCI is exploring the agent in collaboration with Kite Pharma, Inc, a Santa Monica, California-based company that plans to seek investigational new drug status for KTE-C19 from the FDA later this year.

Two other companies, Juno Therapeutics and Novartis, have formed unique partnerships with academic institutions to develop other CAR T-cell therapies that target CD19 in hematologic malignancies. In July, Novartis’ CTL019 became the first CAR therapy to receive a breakthrough therapy designation from the FDA.

Rosenberg, who was honored as a Giants of Cancer Care award winner last year for his pioneering work in the field of anticancer immunotherapies, put the findings about KTE-C19 into perspective in this interview.

OncLive: Please put the latest findings about KTE-C19 into the context of recent CAR research.

Rosenberg: The first report of the use of a chimeric antigen receptor— that is, gene-engineered cells— for the treatment of patients with B-cell malignancies was published in Blood in 2010.² That was of a single patient who showed a dramatic response of very bulky disease—who, incidentally, remains progression free after two cycles of treatment now more than five years later.

After that, both we and several other groups reported additional patients who could respond, but these reports were predominantly in patients with indolent lymphomas that are less aggressive and slower growing, in chronic lymphocytic leukemia which also is slower growing, or in children with acute lymphocytic leukemia.

However, the patients that we are concentrating on now, and are reported in this paper along with others, are patients with aggressive DLBCLs that are refractory to chemotherapy, and very few of those patients ever experience long-term survival. And in that group, there were seven of those patients with DLBCLs, and four of those seven had complete regression of all of their disease including three with ongoing complete regressions.

So, one of the pieces of information here, in addition to increasing the number of patients treated with this gene therapy, is now the first report of patients with this aggressive kind of lymphoma that also can respond to this treatment.

How was response defined?

We used the Cheson criteria, the accepted response criteria for patients with lymphomas. To be called a complete responder, patients must have tumor shrinkage that includes a negative PET scan study, which is the most sensitive technique for detecting even tiny amounts of residual lymphoma. If the patient had major reductions of tumor, but the PET remained positive, then it is a partial response. But if there is no change or if it is mixed—some lesions decrease and some grow—then it is a nonresponse.

Were you able to get a clearer picture of which patients might be more likely to respond to CAR therapy?

So far, we have treated patients with indolent lymphomas, aggressive lymphomas, and chronic lymphocytic leukemia and we have seen complete regression in each of those categories. It looks like any tumor that expresses CD19, which is most B-cell malignancies, is capable of responding to this treatment.

Does that mean there is not a need or perhaps a less pressing need for biomarkers to predict response?

Well, the main biomarker is the expression of CD19. We don’t have biomarkers other than that that might predict response yet. But then again, a relatively small number of patients have been treated.

Please describe the toxicities that patients treated with KTE-C19 encountered.

In these 15 patients, there was one treatment-related mortality of a young woman who had very extensive disease in her chest, who recovered from the treatment well and, the day she was scheduled to go home, had cardiac arrest. That was likely due to an arrhythmia possibly due to the large of amount of disease that she had in her mediastinum.

In the remaining patients, the toxicities were quite manageable. Some patients got confused, but that was temporary. We measure cytokines that are released into the serum of all patients and some cytokines can cause hypotension. But again, this can be successfully managed.

Do you have any thoughts at this point about where CAR therapy might fit into the treatment timeline for these tumor types?

Right now, we are only allowed to treat patients who have been through conventional treatments and are refractory to response to those treatments. So, we are treating patients quite late in the stage of their disease. One of the patients [in the latest study] who had a complete response had 10 prior therapies; another had 12 prior therapies. As we learn more about how effective it is, we will hopefully be able to move it earlier in the natural history of the disease.

What are some of the significant research questions about CAR therapy that remain to be answered?

We are still working hard to figure out the appropriate preoperative chemotherapy regimen that might be suitable. We are trying to see if lower cell doses can still be effective and reduce some of the toxicities, so we are lowering the numbers of cells that we give and looking at less intensive preoperative regimens.

We are also looking at whether or not there are cell subpopulations such as naïve cells or less differentiated cells that have a higher capacity to divide and might be a better source of patient cells into which to introduce the genes.

So, we are looking at a whole variety of ways to improve upon these early results.

Is there anything else that practicing oncology specialists should know about CAR therapies?

We are actively recruiting patients to our current clinical trial and we would be delighted to see any patients with these aggressive B-cell lymphomas for this trial (NCT00924326).

The number of our referral office to which the doctors can call is (301) 451-1929.

Dr Rosenberg can be reached at sar@mail.nih.gov.

References

1. Kochenderfer JN, Dudley ME, Kassim SH, et al. Chemotherapy-refractory diffuse large B-cell cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor [published online August 25, 2014]. J Clin Oncol. doi: 10.1200/JCO.2014.56.2025.
2. Kochenderfer JN, Wilson WH, Janik JE, et al. Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19 [published online July 28, 2010]. Blood. 2010;116(20):4099-4102.