Jul 17, 2022

Chimeric-Antigen Receptor “CAR” T cells have achieved unparalleled success in treating patients with hematologic malignancies, such as leukemia, lymphoma, and myeloma. Particularly, T cell redirection to target the B cell antigen CD19 by anti-CD19 CAR T cells has led to durable responses in patients with refractory leukemia and lymphoma¹. However, despite these achievements, the effectiveness of CAR T cells against solid tumors lags, making investigators ask what can be done to replicate the success seen in liquid tumors?

Several properties of solid tumors are directly connected to CAR T cell failure in this setting. Therefore, new approaches are being developed that may help address the challenging solid tumor landscape and expand the effectiveness of engineered T cells².

Exploring new targets in solid tumors- Limitations in available antigens for specific targeting of solid tumors reduce CAR T cell treatment opportunities. Thereby, solid tumor antigen selection is often limited to tumor-associated rather than tumor specific antigens. Although overexpressed in solid tumors, tumor-associated antigens are not exclusive to tumor tissue and are often expressed at low levels in healthy tissues. Thus their targeting with CAR T cells may lead to unwanted off-tumor on-target toxicity. A new approach under clinical study is evaluating anti-Claudin-6 (CLDN6) CAR T cells to treat solid tumors³.

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Improving antigen detection- Antigen heterogeneity, tumor-associated antigens expressed by only a subset of tumor cells, and low-density antigens present obstacles to the success of CAR T cells in solid tumors. Several strategies may be leveraged to improve antigen detection. For example, as Michel Sadelain shared, clinical outcomes may improve by targeting multiple antigens within a tumor with different CAR T cells, each with a different antigen specificity, or by leveraging dual-specificity CAR T cells. Additionally, co-expression of a Chimeric Co-stimulatory Receptor (CCR) supports improved antigen detection, increasing CAR’s cytotoxic activity.

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Lastly, the use of T cells engineered by re-directing the T cell receptor’s (TCR) antigen specificity, such as the newly designed HLA Independent T cell receptor (TRAC-HIT) or HIT T cells, enable increased sensitivity and lysis activity under conditions of low antigen expression⁴.

Increasing CAR T cell persistence- The intrinsic properties of the solid tumor microenvironment, such as the presence of immunosuppressive cells (e.g., myeloid-derived suppressor cells) and soluble molecular factors (e.g., cytokines), play a role in the survival, infiltration, and activity of CAR T cells, thus limiting their functional persistence^{1, 5}. A new approach promoting efficient CAR T cell engraftment relies on a boosting strategy enabled by an in vitro transcribed (IVT) mRNA vaccine. Following CAR T cell infusion, systemic administration of an IVT mRNA vaccine liposomal formulation targeting antigen-presenting cells drives CAR target expression and stimulates CAR T cell expansion.

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Developed by BioNTech, BNT211 consists of autologous CAR T cells targeting CLDN6 and an mRNA vaccine encoding CLDN6 (CAR-T Cell Amplifying RNA Vaccine or CARVac). CARVac targets antigen-presenting cells (APCs) in lymphoid tissue to express and present CLDN6. Phase 1/2 studies are currently testing the safety and efficacy of anti-CLDN6 autologous CAR T cell infusion and CARVac. This combined anti-CLDN6 CAR T and mRNA boosting strategy aims to improve expansion, persistence, and overall CAR T cell function.

Regulating CAR T cell activity- Increasing CAR T cell potency in solid tumors to cope with antigen expression limitations raises new safety concerns. Because enhanced CAR T cell cytotoxic efficacy may spill into healthy tissues, leading to on-target yet off-tumor toxicities, new approaches are desirable to help prevent such adverse events. Therefore, various strategies have been developed to regulate CAR T cell activity. One new system leverages the co-expression of a protease (NS3 from the hepatitis C virus) and a CAR engineered with an NS3 cognate cutting site, such that CAR T cells usually remain entirely silenced. Nevertheless, the presence of an NS3 protease inhibitor, which prevents proteolytic cleavage, enables fully functional CAR signaling and CAR T cell activation.

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The Signal Neutralization by an Inhibitable Protease (SNIP)-CAR T cells show efficient anti-tumor activity with better survival and reduced toxicity than conventional CAR T cells in an in vivo toxicity model⁶. SNIP CAR T cells benefit from transient resting periods, which enable enhanced potency. As shared by Mackall, “remote-controlled CARs provide an opportunity to increase potency and diminish toxicity.”

Overall, from leveraging new antigens in solid tumors to improving the fitness and regulating the activity of engineered T cells, investigators are developing new strategies to empower autologous T cell immunotherapies to more effectively target solid tumor nuances.

Reference

• Patel, U. et al. CAR T cell therapy in solid tumors: A review of current clinical trials. eJHaem (2022)
  doi:10.1002/jha2.356.
• Titov, A. et al. Advancing CAR T-cell therapy for solid tumors: Lessons learned from lymphoma treatment. Cancers (2020) doi:10.3390/cancers12010125.
• Reinhard, K. et al. An RNA vaccine drives expansion and efficacy of claudin-CAR-T cells against solid tumors. Science (80-. ). (2020) doi:10.1126/science.aay5967.
• Mansilla-Soto, J. et al. HLA-independent T cell receptors for targeting tumors with low antigen density. Nat. Med. (2022) doi:10.1038/s41591-021-01621-1.
• Pietrobon, V. et al. Improving car t-cell persistence. International Journal of Molecular Sciences (2021)
  doi:10.3390/ijms221910828.
• Labanieh, L. et al. Enhanced safety and efficacy of protease-regulated CAR-T cell receptors. Cell (2022)
  doi: 10.1016/j.cell.2022.03.041.