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Potential Solutions to the Roadblocks of Allogeneic CAR T-Cell Therapies

This post is written by FPA intern Nathan Ackermann

Chimeric antigen receptor T-cell (CAR T) therapy is a cancer treatment that shows much promise, achieving extended remission in 30-40% of patients treated in hematological malignancies. This therapy is created by genetically engineering a patient’s T-cells to better recognize and ultimately fight cancer. However, there are several roadblocks to its widespread use; one of the biggest roadblocks is patient wait time. Because this is a cellular therapy derived from the patient’s cells, it can take weeks for them to receive treatment, invaluable time for many in the battle against cancer. Additionally, while it is a rare occasion, the manufacturing process can fail, causing the process to repeat and the patient’s wait time to double.

Currently, allogeneic CAR T therapies are in development to ease these burdens by providing an off the shelf solution to CAR T therapy. The cells harvested from one donor will be able to be used for a much wider patient population, allowing for immediate access as well as lower stakes manufacturing. With such innovation comes new problems to be solved including:

· Graft versus host disease (GVHD) - a complication hallmark to allogeneic therapy attempts. This is when the donor cells end up attacking the host’s cells and tissues because they recognize them as foreign.

· The reverse of GVHD - this is when the host’s cells recognize the therapeutic cells as foreign they will attempt to clear the body of them, limiting the persistence and therapeutic effect of these cells.

Of the hundreds of CAR T companies out there, this article profiles four companies’ allogeneic therapies in Phase 1. Outlined below their differing strategies to mitigate these problems are compared and contrasted.

Celyad – Mont-Saint-Guibert, Belgium

Celyad is developing autologous and allogenic CAR T therapies for both liquid and solid tumor indications. Their allogeneic program revolves around a technology called TIM or TCR Inhibitory Molecules to address the two challenges raised above. The TCR is the receptor on T-cells responsible for detecting antigen present on cell surfaces and determining if it is self or foreign. If foreign, the immune system reacts and attempts to clear the foreign body. TIM’s purpose is to silence the TCR so that they do not recognize anything as foreign and attempt to clear the body of it. CAR T therapies recognize cancerous cells through a CAR, or in Celyad’s case the naturally occurring receptor NKG2D, rather than the TCR. This allows the therapeutic cells to target and attack cancer cells while the TCR is silenced. Another interesting aspect of this approach is that the therapeutic cells express these TIMs. This can allow for silencing of both host and donor TCRs. With both TCRs “shut off,” there is no way for either side to attack the other. This effectively kills two birds with one stone and solves both aforementioned problems; an interesting strategy as other approaches take an action per problem.

Cellectis – Paris, France

Cellectis is a gene-editing company that is focused on developing allogeneic CAR T therapies. Cellectis calls its gene-editing based therapies “UCARTs” or Universal Chimeric Antigen Receptor T-cells. Cellectis has three wholly-owned candidates and 3 others being jointly developed and exclusively licensed by Servier and Allogene. Cellectis’ approach to prevent GVHD is to remove the TCR through their gene-editing technology, which prevents the recognition of host cells as foreign bodies. Their approach for therapeutic cell persistence in the face of the host immune system is not as eloquent, however it is still effective: Rather than selectively mask the therapy from the host immune system, they diminish the host immune system’s ability to detect or attack the therapy. Prior to therapy there is a lymphodepletion regimen to rid the body of its normal lymphocyte population, traditionally done to boost efficacy of CAR-T therapies. However, here it can additionally be seen as a strategy to rid the body of the cells that would detect the therapy as foreign and clear it from the body.

Allogene – South San Francisco, California

Allogene is in collaboration with and an exclusive licensee of Cellectis technology with Servier. Allogene has three top clinical candidates directed at hematological malignancies and a pipeline of preclinical-stage therapies for both liquid and solid tumors. What will differentiate their strategy from others is their anti-CD52 monoclonal antibody (ALLO-647) and their approach for therapeutic cell persistence. Allogene, like other allogeneic CAR T therapy companies, knocks out the TCR to prevent GVHD but they additionally knock out CD52 in their engineered cells. This turns ALLO-647 into a selective immunosuppressive treatment, because now only the host’s immune cells express CD52. This not only enables the engineered cells to persist through ALLO-647 treatment, but also solves the problem of therapeutic cell persistence in the face of the host immune system by suppressing it. With this approach, which is more nuanced than that of Cellectis, if host T-cell populations begin to regrow, the attack on therapeutic cells can be kept at bay with re-administrations of ALLO-647, while not ridding the body of the therapeutic cells like a generic lymphodepletion regiment would.

CRISPR Therapeutics – Cambridge, Massachusetts

CRISPR Therapeutics is a company tackling a range of indications through CRISPR/Cas9 gene editing including allogenic CAR T therapies in development, two in clinical stage and other preclinical candiates targeting both liquid and solid tumors. The approach taken by this company includes the insertion of the CAR and the knockout of both the TCR as well as the class I major histocompatibility complex (MHC I), performed through CRISPR/Cas9 gene editing. This knockout of the TCR prevents GVHD. The knockout of MHC I serves as their approach to allow the cells to survive in the face of the host immune system. The MHC is what traditionally presents antigen, self or foreign, to T-cells when bound through the TCR. The bound cell is then determined to be presenting self or foreign antigen, indicating an infection or foreign body, signaling if the T-cell should attack in response. By knocking this complex out CRISPR is attempting to avoid T cell detection in order for the therapeutic cells to avoid clearance.

These companies, and many more, are developing a myriad of approaches to prevent the body from reacting to allogenic solutions. While the companies mentioned above are only in Phase 1, forthcoming data may illuminate which strategy taken will be the path of least resistance. This could be a hint for other companies in the earlier stages to follow. It remains to be seen if allogeneic solutions can solve these problems and leapfrog over current autologous treatments. However, if these companies are successful in solving these problems, time to patient will be significantly reduced when compared to their autologous counterparts. This will additionally allow for lower stakes manufacturing without a life dependent on each batch created. Furthermore, all of these factors could allow for a lower price point on these therapies with the ability to scale manufacturing to allow for the treatment of many patients per batch. If all of these goals are achieved it could increase the utilization of this form of therapies in turn driving reimbursement, helping launch cellular therapies into the mainstream.

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