Novel CAR T-cell Combos on Horizon for Hematologic Malignancies

Krishna Komanduri, MD

Novel combination approaches are being explored that hope to capitalize on the high rates of complete remissions seen with CAR T-cell therapies for patients with hematologic malignancies, according to an OncLive Peer Exchange labeled Evolving Treatment Paradigms for B-Cell non-Hodgkin Lymphoma that was led by Krishna Komanduri, MD, from the Sylvester Comprehensive Cancer Center.

Among the strategies discussed were those involving CAR T-cell therapies and immune checkpoint inhibitors or the BTK inhibitor ibrutinib (Imbruvica). Data from large prospective clinical trials assessing the combinations are not yet available, but promising early findings from small studies were presented at the 2016 ASH Annual Meeting. Specifically, there were intriguing signs of enhanced efficacy along with the demonstration of a tolerable safety profile for those with chronic lymphocytic leukemia (CLL) who were refractory to ibrutinib.

"There’s several abstracts and papers that have been published that small molecules can restore T-cell health, and ibrutinib has the ability to do that and to make CAR-T cells work well. They’ve worked better both in preclinical models and now this is being tested in studies," said John Byrd, MD, from The Ohio State University, during the discussion.

In a presentation at the ASH Meeting, 24 patients with CLL who were heavily pretreated with a median of 5 prior therapies (range, 3-9) received the CD19-directed CAR T-cell therapy JCAR014. Of those enrolled, 23 had high-risk cytogenetics and 6 were venetoclax-refractory. At the time of data cut-off, 23 patients were evaluable for efficacy, 17 of which had bone marrow disease at the time of study initiation. These patients received lymphodepleting chemotherapy with fludarabine and cyclophosphamide.

Overall, 88% of patients with CLL in their bone marrow had a complete remission by flow cytometry. By IgH deep sequencing, which was available for 14 patients, 50% had no detectable disease on scans (n = 7). These individuals all remained alive and progression free at up to 26 months’ post treatment (range, 3-26).

Overall, 8% of patients developed grade 3 to 5 severe cytokine release syndrome (CRS) and severe grade 3 to 5 neurotoxicity was experienced by 25% of patients. There was 1 treatment-related death, which was caused by grade 5 CRS and cerebral edema.

"[CAR T-cells] still get that critical question [in CLL]—is this going to be curative or not? And until we get that answer, it’s going to be hard to see doing this approach until patients are at a more advanced stage in their disease," noted Byrd.

A potential strategy behind a hard-hitting combination approach is to get the patient into a complete response so that potentially curative transplant can be utilized. With modern techniques, transplants are possible for most patients, explained Leo I. Gordon, MD, during the discussion.

"Allogeneic transplant is still a curative treatment for a significant number of patients," said Gordon, from the Robert H. Lurie Comprehensive Cancer Center. "With non-ablative allogeneic transplants we can treat people into their 70’s and donor availability isn’t so much a problem, I mean most, we can estimate now 70% of patients ought to have a donor when you combine haploidentical matched siblings or matched unrelated donors."

Other studies are also beginning to assess CAR T cell therapies with PD-1 inhibitors. Trials are under way exploring nivolumab (Opdivo) with a CAR T cell therapy in brain cancer. Additionally, studies are exploring the use of pembrolizumab (Keytruda) following progression on CD19-targeted CAR T-cell therapies for patients with lymphomas (NCT02650999).

"I think what’s interesting is that, if you look at trying to collect the cells and trying to maintain them, the idea of perhaps using checkpoint inhibitors to increase the number of central memory T-cells that you want to collect for this and then to maintain them afterwards might be something that will be added to some of these protocols," said Gordon. "It may increase the efficacy of this approach."

One of the drawbacks to the CAR T-cell therapies are the toxicities, specifically CRS and neurotoxicity. However, the panelists felt that current management approaches can effectively curtail these troublesome adverse events.

"I do think that we are likely to get to the point where we can either predict which patients may have unacceptable rates of neurotoxicity or be able to intervene," said Komanduri. "Very low doses of steroids given preemptively can be associated with decreased rates of CRS and neurotoxicity without compromising the efficacy of those cells. These things give me lots of hope, but there will be I think steps forward and backward on the way."

Turtle CJ, Hanafi L, Li D, et al. CD19 CAR-T cells are highly effective in ibrutinib-refractory CLL. Presented at: 58th American Society of Hematology Annual Meeting & Exposition; December 3, 2016; San Diego, CA. Abstract 56.

At the ASH meeting, Juno Therapeutics, the company developing JCAR014 announced plans to conduct a combination trial exploring the CAR T cell therapy with ibrutinib for patients with CLL. The company expects this trial to launch in early 2017. The company is also considering a study of JCAR017 with or without ibrutinib for patients with CLL.