New Solutions Push the Limits of Engineered T Cells in Solid Tumors

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.

John Haanen, M.D., Ph.D.

John Haanen, M.D., Ph.D.,
Medical Oncology Department, Netherlands Cancer Institute, AACR 2022 Clinical Trials Plenary Session.

“Claudin-6 is absent in adult healthy tissue as it’s silenced during organogenesis, various cancers can express Claudin-6, and especially it’s seen in highly unmet medical needs cancers such as testicular cancer and ovarian cancer.”

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.

Michel Sadelain, M.D., Ph.D.

Michel Sadelain, M.D., Ph.D.,
Memorial Sloan Kettering Cancer Center, NY, at AACR Annual Meeting 2022, Adoptive Cellular Therapy: Treatment for the Masses.

“The CARs that utilize the CD28 co-stimulatory domain are usually and probably generally more sensitive than 41BB CARs.”

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 persistence1, 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.

Michel Sadelain, M.D., Ph.D.

Michel Sadelain, M.D., Ph.D.,
Memorial Sloan Kettering Cancer Center, NY, at AACR Annual Meeting 2022, Adoptive Cellular Therapy: Treatment for the Masses.

“Display of this CAR T cell antigen supported engraftment of the CAR T cells and further activation of anti-tumor activity.”

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.

Crystal Mackall M.D.

Crystal Mackall M.D.,
Stanford Center for Cancer Cell Therapy Director, AACR 2022 CAR T cells for Solid Tumors: Bullish or Bearish?

“We developed this first as a safety switch, but what we were surprised to see is that it is much more potent in all the solid tumor models that we tested.”

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.

IVT mRNA Therapy Modalities poster

GenScript Gene & Cell Engineering Virtual Summit


  • Patel, U. et al. CAR T cell therapy in solid tumors: A review of current clinical trials. eJHaem (2022)
  • 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)
  • 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.

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