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In quick succession this summer and fall, the FDA granted the first two approvals of CAR T-cell therapy for malignant diseases: tisagenlecleucel (Kymriah) in late August for children and young adults with relapsed/refractory acute lymphoblastic leukemia (ALL) and axicabtagene ciloleucel (axi-cel, Yescarta) in October for patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Click here to read 名媛直播's original story. In this update, we report on how clinicians view the future of this type of gene therapy.

Different hematologic malignancies and different antigen targets head the wish list for clinicians, researchers, and developers of chimeric antigen receptor (CAR) T-cell therapy. Developments in the short time since the therapies' approval show progress toward both of those goals. However, most experts in the field remain cautious, if not skeptical, about the potential for translating CAR T-cell therapy success in hematologic malignancies to solid tumors.

A study reported at the recent American Society of Hematology (ASH) meeting provided clear evidence that CAR T-cell therapy will continue to move forward as a potentially effective option for patients with hematologic malignancies. The study involved a different disease (relapsed/refractory myeloma) and a different antigenic target (B-cell maturation antigen), but the results were impressive: 17 of the first 18 patients treated had objective responses, including 10 complete responses, the longest still ongoing at 68 weeks.

"It is working better than I expected," National Cancer Institute researcher James Kochenderfer, MD, said during an ASH press briefing. "These patients had a median of seven different lines of therapy, and their disease was progressing."

Commenting on the study, Henry Fung, MD, of Fox Chase Cancer Center in Philadelphia, said, "When we treat groups of people that have been so heavily treated with previous lines of therapy, if we get a response of 30%, we are jumping up and down. So this is pretty darn good."

Wanted: More Antigens

Initial clinical experience with CAR T-cells involved patients with advanced ALL and and DLBCL and focused on the B-cell antigen CD19. In an interview with 名媛直播, Kochenderfer said antigen-discovery research holds the key to improving the efficacy of CAR T-cell therapy and expanding its application to other diseases.

"The main thing we need to do is target more antigens," he said. "We need to target more than one. Some people are already doing studies targeting two antigens. We're doing preclinical studies targeting CD19 and CD20. Others are studying the targeting of CD19 and CD22 at the same time."

Kochenderfer's team at NCI also has a focus on CD30, which is expressed almost ubiquitously on Hodgkin's lymphoma cells. Though many patients with the disease achieve objective responses with conventional therapies, the responses are often short lived. Investigators have begun enrolling patients in a clinical trial evaluating anti-CD30 CAR T-cell therapy aimed at achieving a higher rate of complete responses that also are durable.

CAR T-cell researchers have had their eyes on CD20 for more than a decade, said Brian Till, MD, of Fred Hutchinson Cancer Research Center in Seattle. Targeting CD20 in lymphoma already has a successful precedent in the monoclonal antibody rituximab (Rituxan). Though not as ubiquitous as CD19, CD20 is expressed by lymphoma cells almost as often.

"Half or more of patients don't get sustained complete remissions (with anti-CD19 CAR T-cell therapy), so there's room for improvement," said Till. "We're hoping that [anti-CD20 CAR T-cells] will have similar efficacy, and we would love for the therapy to turn out better than CD19 CAR T-cell therapy."

With respect to potential roles for CD20-targeted CARs, Till said the therapy might be used in combination with CD19-targeted therapy to reduce the risk of antigen loss or escape. Alternatively, anti-CD20 therapy might provide a useful backup when CD19 therapy fails to achieve a response or achieves a suboptimal response. Targeting more than one antigen might also reduce the toxicity of CAR T-cell therapy (including cytokine release syndrome) by minimizing the treatment's off-target effects.

Several research groups are developing bispecific CAR T-cells, which target two antigens with a single cellular construct. Till acknowledged some investigators' enthusiasm for bispecific therapy, but he said squeezing material for two antigens into such a limited space "can be tricky."

"If it's successful, it could simplify things and replace the need for combination therapy," he said.

Help After Relapse

Early experience with CD19-targeted CAR T-cell therapy showed that a substantial number of patients achieve an inadequate response or no response and others lose the response over time. Recent studies showed that upfront inefficacy or loss of response over time is associated with loss of CD19 expression on the cancer cells. Hence, the interest in identifying and targeting antigenic alternatives.

However, in as many as two thirds of cases, relapse after initially successful CAR T-cell therapy is associated with B-cell expression of the immune checkpoint molecule PD-L1, said Sattya Neelapu, MD, of the University of Texas MD Anderson Cancer Center in Houston.

"PD-L1 is an inhibitory ligand, and treatment with a PD-1 or PD-L1 inhibitor has been shown to overcome the inhibitor effect," said Neelapu. "Some groups have already begun studying combination therapy with axi-cel and a PD-1 inhibitor."

CAR T-cell investigators agree that making the jump from hematologic malignancies to solid tumors remains a work in progress. Success in the treatment of B-cell malignancies owes greatly to the fact that CD19 (and other antigens under evaluation) is expressed exclusively by B-cells, whereas many antigens associated with solid tumors also occur in normal tissue.

"B-cells are sort of collateral damage, and we can live without them," said Till. "That's not true of normal tissues that express antigens associated with solid tumors."

A second obstacle to successful CAR T-cell therapy for solid tumors is that the tumor microenvironment appears to be more "hostile toward T-cells in terms of immune suppression and function," Till added. "Once we know more about how tumors prevent T-cells from working, we might be able to come up with more effective strategies."

As work in many laboratories focuses on expanding and improving CAR T-cell therapy, many investigators have set their sights on earlier use of the existing therapies. Both tisagenlecleucel and axi-cel have approval for use in the third-line setting. Neelapu said enrollment has begun in at least two clinical trials comparing axi-cel and stem-cell transplantation as second-line therapy for certain types of lymphoma. Other investigators hope to expand the therapy to other hematologic malignancies, such as mantle cell lymphoma and indolent lymphomas that relapse or become more aggressive.

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