Combinations Required to Further Advance Adoptive T-Cell Therapy

Cassian Yee, MD

A variety of adoptive T-cell therapy strategies have shown promise in clinical trials with recent FDA approvals granted to chimeric antigen receptor (CAR)-modified T-cell therapies, representing the potential for future combination strategies, according to a presentation by Cassian Yee, MD, in an educational session preceding the 32nd Annual SITC Annual Meeting.

“Combination strategies will be required,” Yee, from the Department of Melanoma Medical Oncology, Division of Cancer Medicine, at the MD Anderson Cancer Center, said during his talk. "This paradigm is important because we've only just started to tap the wealth of potential available for these adoptive T-cell therapies."

The 3 main types of adoptive T-cell therapies discussed by Yee were tumor-infiltrating lymphocytes (TILs), endogenous T cells (ETC), and T cells engineered to express a CAR or T cell receptor (TCR). Each adoptive T-cell therapy approach has demonstrated unique characteristics, he pointed out. In general, these agents are non-cross-resistant with chemotherapy or radiation therapy, they have multiple killing mechanisms, potential for memory of target antigens, and they typically require a single infusion, with on- and off-target toxicities and tumor immune evasion mechanisms representing the largest challenge to overcome.

The CAR T-cell therapies are generating the most excitement, Yee noted. In August 2017, tisagenlecleucel (Kymriah) became the first FDA-approved CAR T-cell therapy, representing a major milestone. This achievement was quickly followed by approval of the CAR T-cell therapy axicabtagene ciloleucel (Yescarta). Tisagenlecleucel is indicated for acute lymphoblastic leukemia (ALL) while axicabtagene ciloleucel is approved for non-Hodgkin lymphoma (NHL).

Both agents demonstrated high levels of clinical activity in phase II studies, with several additional trials ongoing. In the phase II ELIANA trial, tisagenlecleucel demonstrated an objective response rate (ORR) of 82.5% with a complete response (CR) rate of 63% for patients with ALL. In the phase II ZUMA-1 trial, axicabtagene ciloleucel had an ORR of 82% and a CR rate of 54% for patients with NHL.

Both FDA-approved CAR T-cell therapies target CD19. For patients with multiple myeloma, the B-cell maturation antigen (BCMA) has generated the most interest as a potential target. Adoptive T-cell therapies against BCMA are still in early phases of development but early results have shown high levels of very good partial response or better.

Although a major advance, Yee expressed concerns over associated costs. Tisagenlecleucel debuted at $475,000 and axicabtagene ciloleucel was priced at $373,000. Additionally, both agents can be associated with hefty supportive care costs. Rolling this approach out to solid tumors or as a frontline standard of care could represent a potential economic challenge, Yee said. “It is hard to imagine these costs being sustainable, if we're treating tens of thousands of patients,” he added.

TILs and ETCs have not yet gained FDA approvals but promising data are beginning to shape the field. Additionally, the early exploration of these agents as monotherapy sets the stage for future combination strategies.

In a handful of small trials published in 2011 and 2012, the response rates with TILs were consistently around 48% for patients with metastatic melanoma, with a CR rate that fluctuated from 6.5% to 13%. In a trial from 2012 of 93 patients with melanoma pretreated with immunotherapy, responses varied based on the prior therapy administered. For those treated with prior IL-2 or anti-CTLA4 therapy, respectively, the CR rates were 18% and 45%.

ETCs hold the greatest potential for their large TCR repertoire, Yee noted. Additionally, they can be collected from the peripheral blood, offering an accessibility advantage and these cells have simplistic regulatory systems, making them ideal candidates for genetic modification.

MART1-specific interleuken-21 primed T-cells were combined with the anti-CTLA4 inhibitor ipilimumab (Yervoy) in a small trial of 10 patients with metastatic melanoma. At 12 weeks, there were 2 CRs and 1 partial response, with an additional 3 patients having stable disease. The disease control rate was 60%.

There were signs of long-lived T cell memory and responses to non-targeted tumor antigens, a sign of epitope spreading, Yee said. Importantly, he noted, the treatment was given in an outpatient setting. A phase II trial is currently open at MD Anderson to further explore the combination.