BioPharma, Startups

Researchers develop ‘armored’ CAR-T with potential against solid tumors

Mouse model study uses PD-1 antibody technology from Eureka Therapeutics, which is also developing T-cell receptor therapies.

CAR-T cell therapies have made significant strides in the treatment of blood cancers, though they have yet to see the same level of success in solid tumors. But a recently published paper from a preclinical study has shown a potential way to change that.

Researchers at Memorial Sloan Kettering Cancer Center in New York combined CARs with PD-1 checkpoint inhibitor antibodies on the same engineered T cell to create what are sometimes called “armored CARs.” Their research, led by Dr. Renier Brentjens, was published in Nature Biotechnology.

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So far, the Food and Drug Administration has approved two CAR-T therapies – namely Novartis’ Kymriah (tisagenlecleucel), for pediatric acute lymphoblastic leukemia and adult diffuse large B-cell lymphoma, and Gilead Sciences’ Yescarta (axicabtagene ciloleucel), for DLBCL. In addition, numerous PD-1 and PD-L1 checkpoint inhibitors have been approved, including Bristol-Myers Squibb’s Opdivo (nivolumab), Merck & Co.’s Keytruda (pembrolizumab), Roche’s Tecentriq (atezolizumab) and others. However, the immunosuppressive microenvironment of solid tumors limits the ability of T-cell therapies to be successful, while checkpoint inhibitors can cause several immune-related side effects.

The study, in mouse models, used CAR-Ts that attacked CD19 – the same antigen targeted by Kymriah and Yescarta, heavily expressed in ALL and non-Hodgkin’s lymphomas – and MUC16, found in some ovarian and pancreatic cancers. With the cells expressing PD-1 in addition to CD19 or MUC16, the engineered T cells tended to stay around the tumor site, thus potentially avoiding side effects associated with systemic checkpoint inhibition, and also activate nearby T cells, while persisting longer than standard CAR-Ts.

The PD-1 antibody component was developed using Eureka Therapeutics’ E-ALPHA phage display library. Eureka – based in Emeryville, California, near San Francisco – is also developing a T-cell receptor (TCR) program, ARTEMIS, and CEO Cheng Liu said the company is “excited” about applying the PD-1 antibody approach to ARTEMIS. The company closed a $60 million Series D financing round in January to advance the platform, led by Acorn Pacific Ventures and with participation from GP Capital and existing investors.

Efforts to develop armored CARs have been underway for several years, including at Brentjens’ lab. He and others published a paper in early 2014 exploring the idea of armored CARs. In addition, other trials have sought to combine CAR-T therapies with checkpoint inhibitors. For example, Gilead’s Phase I ZUMA-6 study is testing Yescarta and Tecentriq in patients with DLBCL. Early data on six patients from the trial presented at the 2017 American Society of Hematology meeting showed that all of the five who were evaluable for efficacy had a response, including one complete response. In terms of toxicity, about four experienced encephalopathy, and about two had cytokine release syndrome, though there was no evidence of toxicity being worsened due to administration of Tecentriq.

Other CAR-Ts in development include JCAR017 (lisocabtagene maraleucel), under development for non-Hodgkin’s lymphoma by Juno Therapeutics, a Seattle-based company that Celgene bought earlier this year for $9 billion, as well as Cambridge, Massachusetts-based bluebird bio’s bb2121 in multiple myeloma.

Photo: nopparit, Getty Images