Future Looks Bright for CAR T-Cell Therapies in Hematologic Malignancies

Nirav N. Shah, MD

CD19-directed CAR T-cell therapy has demonstrated impressive responses in select patients with refractory hematologic malignancies, and ongoing research may further increase the durability of this clinical activity, said Nirav N. Shah, MD.

One such product, axicabtagene ciloleucel (axi-cel; Yescarta), received approval from the FDA in October 2017 for the treatment of adults with relapsed or refractory non-Hodgkin lymphoma based on early data from the pivotal phase II ZUMA-1 trial. Updated data presented at the 2018 ASH Annual Meeting showed that treatment with the CAR T-cell therapy led to a 2-year overall survival rate of 51% in patients with refractory large B-cell lymphoma. Furthermore, the 2-year progression-free survival (PFS) rate was 39% with the therapy and the median PFS was 5.9 months. At the time of data presentation, a median duration of response with the therapy had not been reached for patients who achieved complete response (CR).^1,2

Additionally, in October 2017, the FDA granted an approval to tisagenlecleucel (Kymriah) for the treatment of patients up to age 25 years with B-cell precursor ALL that was refractory or in second or later relapse. In May 2018, the agency approved this agent for use in adult patients with relapsed/refractory large B-cell lymphoma following ≥2 lines of systemic therapy.

Another CAR T-cell product that is moving through the pipeline is lisocabtagene maraleucel (liso-cel; JCAR017). In patients with high-risk, heavily pretreated chronic lymphocytic leukemia, liso-cel elicited an overall response rate of 81.3% and a CR rate of 43.8%. Data presented at the 2018 ASH Annual Meeting showed that the therapy also was tolerable, with low rates of grade 3 cytokine release syndrome.³

“In the non—Hodgkin lymphoma space, liso-cel is probably the next candidate product that might be up for approval in the next year or 2,” said Shah, an assistant professor of medicine at the Medical College of Wisconsin. “Obviously, the company will make those decisions when the time is right. It will be interesting when we do have [multiple] products readily available. How we choose patients for different products will be a big question.”

In an interview during the 2019 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Shah discussed the promise of CAR T-cell therapy in hematologic malignancies and highlighted recent research exploring sequential CAR-T therapies, armored CAR T cells, as well as other novel approaches.

OncLive: What data have we seen with CD19-directed CAR T cells?

Shah: There are 2 products approved by the FDA, and there are some differences between the them. [This type of therapy] seems to be effective in about 30% to 40% of patients with aggressive large-cell lymphomas. This is a significant advancement from our previous standard of care, but that obviously means that a substantial number of patients still either fail to respond or initially respond and subsequently relapse.

What are the differences between the anti—CD19 products?

CAR T-cells are a biological product, so any changes within the construct of the CAR T cell could theoretically impact safety, efficacy, and toxicity. One of the FDA-approved products is the 4-1BB construct, and there are properties of that which are different from the other FDA-approved product, which is a CD28 CAR T-cell product. Unfortunately, without a head-to-head trial, it is very difficult to make cross comparisons. However, there are possible differences within the toxicity profiles of these products.

What do the updated data with these products presented at the 2018 ASH Annual Meeting suggest about their durability? We saw updated data for the product axi-cel, which is an anti-CD19 CAR T-cell product. We now have a 2-year update, which shows that about 39% of patients remained in remission, which is very encouraging. It shows that not only is CAR T-cell therapy effective, but there is some durability to it. The problem is that this [response is] still not long enough. What does cure mean to a patient? It means the disease never comes back. We are looking forward to 5-, 10-, and 15-year follow-up as time passes.

Will combination strategies be explored with this type of therapy?

Absolutely, and that's sort of where the field is moving. Right now, we have made great advances with the single targeting of CD19. However, many research groups, including ours at the Medical College of Wisconsin, are exploring the role of dual targeting or bispecific targeting. We are seeing if targeting more than 1 B-cell receptor will improve upon the current standard of care.

How would you advise managing associated toxicities?

Currently, academic centers are well-equipped to handle these types of toxicities. Many of us are participating in clinical trials or developing our own clinical trials. Over time, it is possible that some of these therapies will disseminate into larger, community-type oncologic centers, so with greater experience, we will get more comfortable with managing the toxicities. Like any other therapy, there is a subset of patients who get really sick after receiving CAR T cells. Some patients can die. However, we've learned from multiple clinical trials that [most of] these toxicities are manageable and reversible.

Is sequential CAR T-cell therapy on the horizon?

Absolutely. For patients who are relapsing after CD19-directed CAR T-cell therapy, there are already trials open that are investigating the targeting of other antigens to get a sequential CAR T-cell therapy if they have failed a prior one.

What other trials are you excited about?

There is so much going on in the field of CAR T and cellular therapy. There are armored CAR T cells, which is a different form of CAR T cells [that may be] more effective and more persistent. Those [products] are being investigated in clinical trials. We talked about dual or multi-targeted CAR T cells, sequential CAR T cells, and some researchers are looking at a different type of immune effector cell called natural killer (NK) cells. CAR NK is something up-and-coming and may serve as another option for patients who have failed traditional options.

Could you expand on that mechanism?

NK is another type of immune effector cell that can be genetically modified and turned into a CAR. There are some advantages to NK cells—they can sort of be an off-the-shelf product because they don't elicit as much of an immune response within a patient. An off-the-shelf CAR T-cell product would have great advantages because then a product would be readily available when the patient needed it, unlike the current approach where you have to collect the T cells from the patient and do the genetic modification.

What is your take-home message to your colleagues?

CAR T cells are incredibly exciting, and they are changing the way we are thinking about liquid cancers. Eventually, [this approach] may move into solid malignancies. What's important to community doctors is referring these patients early to a center that provides cellular therapy for a multitude of reasons. One, we will be able to appropriately discuss the available options and two, there are so many clinical trials in this space that getting patients at first relapse may offer them [additional treatment] opportunities.

References

1. Neelapu SS, Ghobadi A, Jacobson CA, et al. 2-year follow-up and high-risk subset analysis of Zuma-1, the pivotal study of axicabtagene ciloleucel (Axi-Cel) in patients with refractory large B cell lymphoma. Blood. 2018;132(suppl 1):2967. doi: 10.1182/blood-2018-99-222368.
2. Locke FL, Ghobadi A, Jacobson CA, et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicenter, phase 1-2 trial. Lancet Oncol. 2019;20(1):31-42. doi: 10.1016/S1470-2045(18)30864-7.
3. Siddiqi T, Soumerai JD, Wierda WG, et al. Rapid MRD-negative responses in patients with relapsed/refractory CLL treated with liso-cel, a CD19-directed CAR T-cell product: preliminary results from Transcend CLL 004, a phase 1/2 study including patients with high-risk disease previously treated with ibrutinib. Blood. 2018;132(suppl 1):300. doi: 10.182/blood-2018-99-110462.