Building a bulletproof CAR? Scientists engineer a built-in PD-1 shield

by John Carroll
July 26, 2016

CAR-Ts won’t be on the market before next year, but the technology arms race inspired by the prospect of a multibillion-dollar market has inspired a group of prominent investigators to design a new, 3.0 model in the lab that includes a built-in checkpoint mechanism. And it worked like a charm in mouse models of solid tumors - a critical hurdle that the key players have been struggling to clear.

Publishing in The Journal of Clinical Investigation, a group including Juno scientific co-founder and Memorial Sloan-Kettering star Michel Sadelain write about their latest genetic engineering project with CAR-Ts, the individually tailored T cells used to assault cancer. The paper explores how they tinkered with various aspects of their third-generation CAR-T. But the key development centered on their use of a viral vector to design a new therapy with a built-in checkpoint mechanism.

The checkpoint drugs - Opdivo and Keytruda and Tecentriq, which unleash an immune system attack on cancer cells - all present problems of their own when used in combination with CAR-T drugs, the researchers note. And that’s something that can be skirted with genetic reengineering.

According to the scientists, this new model CAR-T managed to work longer at a lower dose in solid tumors in mice. Several key elements - persistence, scoring a better hit on a solid tumor, lowering the dose to achieve better safety - are all in play. And the work promises to influence the frantic race to dominate a new and compelling therapeutic blockbuster that can ultimately eclipse the relatively crude first-generation treatments now in pivotal studies.

The study concludes:

“We demonstrate here that CAR T cell therapy and PD-1 checkpoint blockade are a rational combination in a solid tumor model. To directly counteract PD-1–mediated inhibition we used retroviral vectors to combine CAR-mediated costimulation with a PD-1 (dominant negative receptor). This combinatorial strategy (costimulation and checkpoint blockade) enhanced T cell function in the presence of tumor PD-L1 expression, resulting in long-term tumor-free survival following infusion of a single low dose of CAR T cells. Our study is relevant to the clinical practice of adoptive T cell therapy and immediately translational for the following reasons: (a) the costimulatory signaling domains tested - CD28 and 4-1BB - are the 2 costimulatory domains used in ongoing clinical trials ( NCT02414269, NCT02159716, NCT01583686); (b) our models of pleural mesothelioma recapitulate human disease and use large, clinically relevant tumor burdens that elucidate the relevance of T cell exhaustion; and (c) our strategy of potentiating CAR T cells by genetically encoded checkpoint blockade uses human sequences that can be readily applied in the clinic.”

The investigators carefully note that this is not a magic bullet. Other factors are in play that will have to be explored. And reducing a safety threat on one side doesn’t mean that this tactic won’t backfire.

“Because it provides blockade of inhibitory pathways that is limited to a tumor-targeted T cell repertoire, adoptive transfer of PD-1–insensitive T cells may limit the autoimmunity that results from a more broadly applied antibody checkpoint blockade,” they note. “Nonetheless, additional safety strategies are necessary to limit or prevent potential augmented autoimmunity of the genetically modified PD-1–insensitive T cells.”

Of course, any mouse study is just the first step in a process that can lead to a long road of clinical work. Typically, they never survive that process. But this particular project is exceptional, centering on prominent, well-connected investigators like Sadelain, who are already closely involved in Juno’s development effort.

As Kite’s move yesterday to snag new tech underscores, the leaders in the field are acutely aware of the fact that limitations and threats—like the one that claimed the lives of four patients in Juno’s work—have to be overcome before CAR-Ts can reach their full potential.

This is one step that will be closely followed by all.