Expert Considers Potential New Directions for CAR T-Cell Therapies

Abhinav Deol, MD

Chimeric antigen receptor (CAR) T-cell therapy has been a great step forward for the treatment of relapsed/refractory adult diffuse large B-cell lymphoma (DLBCL) and children and young adults with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL).

However, Abhinav Deol, MD, said medical science must find a way to make this approach available to more patients and expand treatment beyond hematologic malignancies.

The CAR T-cell products currently approved by the FDA—tisagenlecleucel (Kymriah) for both ALL and DLBCL populations and axicabtagene ciloleucel (axi-cel; Yescarta) for DLBCL—have delivered significant results. However, these products also come with unique challenges including toxicity, such as cytokine release syndrome (CRS), access, and cost.

“These drugs are very expensive. The ALL product costs about $475,000 and the DLBCL products cost about $375,000,” Deol, associate professor with Karmanos Cancer Institute, said. “That is just the cost of the cells. This does not include the management of toxicities, and it's not out of the ordinary for the patient's total bill to be close to $500,000 when they're done with treatment. There needs to be a little more research into making this treatment more affordable so that more patients can be treated.”

OncLive^®: What are some of the key take-home points of your presentation on CAR T-cell therapy?

In an interview during the 2018 OncLive^® State of the Science Summit^TM on Hematologic Malignancies, Deol discussed the basics of CAR T-cell therapy, potential new directions for these products, and the possible impact new products might have on the field.Deol: I wanted to give people an overview in terms of what CAR T cells are, because it's a relatively new modality of treatment for management of patients with different types of cancers. There are some unique challenges in terms of which patients are appropriate to get CAR T-cell therapy; there are some toxicities that are unique to CAR T cells.

How would you describe the experience of seeing the rise and spread of CAR T-cell therapy?

What factors do you consider when determining whether a patient is eligible for CAR T-cell therapy?

What are the most common safety issues associated with CAR T cells and how do you manage them?

Right now, CAR T cells are FDA approved for ALL up to the age of 25 for patients who failed conventional chemotherapy or transplant, and also for DLBCL for patients who failed at least 2 lines of therapy or who are ineligible for an autologous stem cell transplant. Finally, I wanted to discuss future interesting research in some of the other diseases, such as multiple myeloma, and some of the challenges—not only the scientific challenges, but also the costs associated with treatment.It is very exciting. My training, initially, was in immunotherapy and it's very satisfying to see an effective immunotherapy win approval. These are patients who didn't have any clinical trials available; some of them had failed on novel drug combinations and now they're cured of disease. Unfortunately, it doesn't work for everybody—not every patient is able to get this treatment because of organ function requirements and some of the other involvement, especially if they have central nervous system involvement. It has not been studied in that setting, but hopefully as we learn more about these therapies, we can use them in a broader sense in terms of having more patients we can take through these treatments safely and effectively.The important thing is to first determine whether the patient meets criteria for the FDA-approved indication, because insurance companies carefully look at that to determine whether they'll cover someone treated with CAR T cells. That has been a challenge. Also, one must make sure the patient has adequate organ function. We need to make sure the patient's lungs work well, the heart works well, and they didn't have significant kidney dysfunction. These toxicities that happen after the infusion of CAR T cells require good cardiovascular system that can handle high fevers and CRS, so that the patient can make it through the initial complications.We worry not only about the associated chemotherapy side effects—nausea, vomiting, hair loss—because they do get some low-dose chemotherapy prior to getting CAR T cells, but the unique side effects we recognize with CAR T cells include CRS and neurological toxicities. The CRS can be, in some mild cases, characterized by fevers, chills, slightly low blood pressure that responds to intravenous fluids to, in extreme cases, fevers that are very high, and blood pressure that drops low enough to require medication.

What type of overall response do these products induce?

In terms of neurological toxicity, some patients don't have any. Others might have mild confusion. In the severe extreme, patients can become comatose or have seizures as a result of neurotoxicity. Thus far, the companies have been very careful in terms of having sites that have experience and adequate training to treat patients. They're limiting the first roll-out to sites that are able to manage these toxicities, because it is a multimodality management.The reason these products were approved was based on results of clinical trials. ZUMA-1 [with axi-cel] looked at relapsed/refractory DLBCL and the overall response rate was close to 80%. However, the complete response (CR) rate around 12 to 18 months is approximately 40% to 45%. There are patients who respond, but unfortunately did relapse after treatment. Therefore, there needs to be more research into preventing relapse and keeping these patients in remission.

Tisagenlecleucel was also explored in a multicenter study that looked at a few hundred patients who were treated with the product; their response rates were around 55% to 60% with, again, long-term CR rates in the 40% to 45% range. We have seen some differences in terms of the upfront responses, but if you look at the long-term CR data for both studies, they seem to be similar in the 40% to 50% range.

There is another product on the horizon, which is being investigated by Juno Pharmaceuticals (lisocabtagene maraleucel; JCAR017), and that should hopefully be approved in the next few months to next year. Primary studies seem to point to similar efficacy.

What is the rationale supporting the combination of atezolizumab plus axi-cel in DLBCL that is currently being investigated in the ZUMA-6 trial?

Are investigators exploring more combinations of CAR T-cell products?

The next challenge will be to see whether all of these CAR T-cell products have different toxicities. Earlier studies might point toward slightly different toxicity profiles with different agents, but these have not been compared in a head-to-head study. Also, the toxicity management, scaling, and staging criteria were a bit different in each study.That study was initiated because some patients relapsed after getting initial CR. When we looked at the biopsies, we found that some of those patients had lost CD19 expression, so the tumor grew. The higher number of patients still had CD19-expressing tumors, but they also had lower expression of PD-1 on the tumor surface. That led to the hypothesis that if you can inhibit the PD-1/PD-L1 axis along with CAR T cells, you might have more sustained remissions. We expect to see data presented over the next few months.There is research now looking at using 2 types of CAR T cells so the tumor doesn't have escape. Those data seem to be in early stages in ALL, where investigators have looked at targeting not only CD19 but also CD22. In ALL, the relapse seems to be more because of CD19 escape; the tumor loses CD19 expression, but still expresses CD22. Researchers are looking into targeting with both CAR T cells at the same time so the lymphoblastic leukemia cells are eliminated completely and then patients can stay in remission longer.