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Harnessing the power of the body’s own immune system, particularly with the use of chimeric antigen receptor (CAR) T cells, has significantly improved outcomes for patients with certain hematologic malignancies. CAR-T therapy is a cell-based immunotherapy whereby a patient’s own T cells are genetically engineered to fight cancer cells. These genetically modified CAR-T cells seek and destroy cancer cells by recognizing specific antigens on the tumor cell-surface that are otherwise invisible to unmodified T cells. CAR-T cell therapies have achieved success in the treatment of B cell and plasma cell malignancies, with five CAR-T cell products now approved by the US Food and Drug Administration (FDA). However, the track record for CAR-T cell therapies in solid tumors, which account for more than 90% of all cancer fatalities, has not been as impressive to date. There are a variety of reasons for this, relating both to toxicity as well as penetration and activation of CAR-T cells at the tumor site.
A primary challenge to the development of successful therapies for solid tumors is the scarcity of tumor-associated antigens (TAAs) that are absent on normal, healthy tissues. Unlike hematological malignancies, where exclusive tumor-specific antigens have been identified, TAAs of solid tumors are also generally expressed on normal, healthy tissues. There is simply no perfect target or “silver bullet.” “On-target, off-tumor” toxicity occurs when CAR-T cells attack non-tumor cells expressing the target antigen and can lead to severe and potentially life-threatening side effects. The immune-suppressive tumor microenvironment creates further obstacles to CAR-T cells including impairment of T cell infiltration and enhancement of immunosuppressive metabolism. The multiple mechanisms for immunosuppression create physical and biochemical barriers that facilitate rapid tumor progression and limits CAR-T cell efficacy through other biochemical factors.
One strategy to effectively reduce on-target, off-tumor toxicity is to affinity tune CARs precisely so that they kill tumor cells with a high density of surface antigens but spares normal cells with low antigen densities. The majority of CAR-T cell approaches against solid tumors to date have utilized CARs with very high affinity for their targets, raising the possibility of on-target, off-tumor toxicity described above. One other advantage of affinity-tuned CARs is that CAR-T cell activation may become more similar to the natural activation observed in non-modified T cells. Therefore, the development of affinity-tuned CARs is expected to both reduce the side-effects and toxicity compared to current CAR-T therapies and lead to more effective anti-cancer activity.
We and others have shown that compared to high affinity CAR-T cells in animal models the lower affinity CAR-T cells can not only achieve selective killing of tumors but also produce longer-lasting anti-tumor activity without excessive cytokine release. One of our target antigens is ICAM-1, which shows high expression in many tumor types with low level expression in some normal tissues. Importantly, toxicity to healthy cells expressing basal levels of the target ICAM-1, seen with high-affinity CAR-T cells, is averted using CAR-T cells tuned to a lower-affinity. In addition, optimally tuned affinity may prevent T cell exhaustion, increase CAR-T cell longevity, and facilitate serial tumor cell killing. ICAM-1 targeting can be added to other primary targets to overcome antigen heterogeneity in solid tumors as targeted killing by T cells releases cytokines that induce the expression of ICAM-1 in the surrounding tumor cells, preventing an escape route common to most forms of targeted cancer therapy.
Technology has been developed to track the expression of a marker, somatostatin receptor 2 (SSTR2), on engineered CAR-T cells, which can be detected with a clinically approved PET/CT imaging tracer. This tracking system provides information on the spatiotemporal kinetics of the CAR-T cells, showing whether CAR-T cells are multiplying at the site of cancer or in normal tissues. This helps clinicians to diagnose potential cytokine release syndrome or other severe toxicities in patients faster and more accurate than current practice. In the future, SSTR2 has the potential to be used as a safety switch and activity modulator to further increase safety and efficacy of CAR-T therapies. With technological advancements in affinity tuning and real-time tracking of CAR-T cells, the hope is that CAR-T therapy can safely and effectively be applied to treating solid tumors, improve patient outcomes, and avoid the toxicities seen with certain treatments in the clinic.
Eric von Hofe is President & COO, Affyimmune.