CAR T-Cell Therapy in ALL: Formidible Challenges Remain

Adoptive transfer of T cells engineered to express a chimeric antigen receptor (CAR) has emerged as a very promising type of targeted immunotherapy, with some studies showing complete remission rates as high as 90% in relapsed and refractory acute lymphoblastic leukemia (ALL).

“To date, CAR T-cell trials have thus far shown the highest rate of complete and minimal residual disease remission rates of any other agent,” explained Bijal Shah, MD, of Moffitt Cancer Center in Tampa, during the National Comprehensive Cancer Network (NCCN) Annual Conference, held March 22–24 in Orlando, Florida.

New therapies are urgently needed in the setting of refractory/relapsed disease, especially for adult patients. Adults comprise nearly half of patients with ALL, most of whom harbor high-risk mutations that translate into poor long-term survival.

Shah noted that adult ALL “doesn’t get enough attention, but it does account for nearly half of all the all cases that we see.” Adult patients with ALL are more likely to relapse, and their outcomes are typically poor, with an average survival of roughly 40%. “I think we have a lot of room for improvement there,” he said.

Options for patients with refractory and relapsed disease have traditionally been allogeneictransplantation and chemotherapy. More recently, the monoclonal antibodies inotuzumab and blinatumomab have performed better than cytarabine-based chemotherapy. Still, “it’s not easy to get excited about long-term survival improvements of 25%," Shah noted.

CAR T-cell therapies have the potential of improving survival, but there are challenges to this therapy. For one thing, it takes time to “manufacture” the therapy, and this process can take several weeks. It can be difficult to keep a patient’s disease stable during this period. Another issue is age, Shah pointed out. Children do better than adults with this therapy, and as “we decrease the age, the better the response.”

A traditional goal of salvage therapy in the refractory/relapsed population has been to transition patients to transplant, but in trials of inotuzumab and blinatumomab, there has been no clear impact on survival after censoring patients at the time of transplant. In CAR-T therapy trials, transplant rates have been variable.

Shah highlighted a study conducted at Memorial Sloan Kettering Cancer Center (MSKCC), which was a transplant vs no-transplant analysis of 19 patients with morphologic disease prior to CAR-T therapy. No clear survival benefit was observed for transplantation. In a similar study, relapses were more common in patients treated at the National Cancer Institute who were not transplanted, although the impact on survival was unclear.

Dr. Shah also pointed to another recent study from MSKCC, and posed the question, “Should we be worried?” because the outcomes with CAR-T cell therapy were not very encouraging. However, he noted that there was a tendency to treat patients with higher tumor burdens (> 5% blasts), and outcomes in this setting are less than optimal. The more heavily pretreated patients (those who had received four or more lines of therapy), and who comprised about one-third of the cohort, also had worse outcomes.

Toxicity is a significant concern with CAR T-cell therapies, since they have the capacity to elicit not only expected serious adverse events but also unexpected ones, including cytokine release syndrome (CRS), neurologic toxicity, “on target/off tumor” recognition, and anaphylaxis. CRS is the most common adverse event observed with CAR T-cell therapy. It consists of an escalated immune response that, on rare occasions, can evolve into fulminant hemophagocytic lymphohistiocytosis.

Tocilizumab is key to managing CRS, and it should be administered at the first signs of hypotension or fever, Shah explained. He added that his own personal bias is that if CRS does not improve with tocilizumab, “more isn’t going to help. Get the steroids queued up and get ready to move.”

Tocilizumab is also not helpful for neurotoxicity. “Watch for infusion reactions, and don’t forget that these are ALL patients and watch for infections,” he said.

Shah noted that cerebral edema has also been observed in clinical trials-among 6 ALL patients participating in the JUNO trials (and in 1 patient with non-Hodgkin lymphoma treated in the ZUMA-1 phase II registration trial). There were multiple deaths due to cerebral edema in the JUNO trials, but the mechanisms for this side effect, as well as the optimal therapy, remain “elusive,” he said.

In looking to the future, Shah feels that off-the-shelf CAR T-cell therapies will be key to treating more patients, along with improving durability and response, and improving the current toxicity profile. “Post–CAR-T relapse is going to be a big problem,” he said, and the solution to that problem remains unknown.

Novel studies are already underway with the goal of preventing and managing relapse in the context of CAR T-cell therapy.