Treating hematologic malignancies with engineered T cells

Chimeric-antigen receptor “CAR” T cells have achieved unparalleled success in treating patients with hematologic malignancies, such as leukemia, lymphoma, and myeloma. In particular, anti-CD19 CAR T cells have produced long-lasting responses in patients with refractory leukemia and lymphoma by redirecting T cells to target the B cell antigen CD19.1

Nevertheless, despite these successes, CAR T cell efficacy against solid tumors lags, causing researchers to question what more could be done to replicate the success seen in liquid tumors.

The failure of CAR T cells in this situation is directly related to specific characteristics of solid tumors. To address the complex concrete tumor landscape and increase the efficacy of modified T cells,2 new strategies are being created.

Investigating potential targets for solid tumors

Limitations in available antigens for specific targeting of solid tumors reduce CAR T cell treatment opportunities. Thus, as a result, solid tumor antigen selection is often limited to tumor-associated rather than tumor-specific antigens.

Despite being overexpressed in solid tumors, tumor-associated antigens are not exclusive to tumor tissue and are often expressed at low levels in healthy tissues. Therefore, using CAR T cells to target them could result in unintended off-tumor on-target damage. Anti-Claudin-6 (CLDN6) CAR T cells are a new approach being tested in clinical trials to treat solid tumors.3

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

John Haanen, MD, Ph.D., Medical Oncology Department, Netherlands Cancer Institute

Improving antigen detection

The use of CAR T cells in solid tumors is hampered by antigen heterogeneity, tumor-associated antigens expressed by only a portion of tumor cells, and low-density antigens.

To increase antigen detection, a number of techniques can be used. For instance, using separate CAR T cells, each with a distinct antigen specificity, or using CAR T cells with dual specificities could result in better clinical results, as Michel Sadelain highlighted.

Furthermore, enhanced antigen recognition is supported by the co-expression of a Chimeric Co-stimulatory Receptor (CCR), which boosts the cytotoxic activity of CAR.

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

Michel Sadelain, MD, Ph.D., Memorial Sloan Kettering Cancer Center

Last but not least, the use of T cells created by re-directing the TCR’s antigen specificity, such as the recently created HLA Independent T cell receptor (TRAC-HIT) or HIT T cells, enables improved sensitivity and lysis activity in circumstances of low antigen expression.4

Increasing the persistence of CAR T cells

The survival, infiltration, and activity of CAR T cells are influenced by the inherent characteristics of the solid tumor microenvironment, such as the presence of immunosuppressive cells (such as myeloid-derived suppressor cells) and soluble molecular factors (such as cytokines), which restricts their functional persistence.1,5

An innovative method for effective CAR T cell engraftment uses a boosting technique made possible by an in vitro transcribed (IVT) mRNA vaccine. An IVT mRNA vaccine liposomal formulation that targets antigen-presenting cells is then systemically administered after CAR T cell infusion, driving CAR target expression and promoting CAR T cell multiplication.

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

Dr. Haanen

BNT211, created by BioNTech, combines an mRNA vaccine encoding CLDN6 with autologous CAR T cells that are specifically directed against CLDN6 (CAR-T Cell Amplifying RNA Vaccine or CARVac).

To produce and display CLDN6 in lymphoid tissue, CARVac targets antigen-presenting cells (APCs). CARVac and autologous CAR T cell injection directed against CLDN6 is now being evaluated in phase 1/2 trials for safety and effectiveness.

The aim of this combined anti-CLDN6 CAR T and mRNA boosting strategy is to improve expansion, persistence, and overall CAR T cell function.

Controlling CAR T cell activity

To overcome the restrictions on antigen expression in solid tumors, CAR T cell potency has been increased, raising new security issues. New methods are required to help prevent such unfavorable occurrences since improved CAR T cell cytotoxic potency could leak into healthy tissues, resulting in on-target yet off-tumor toxicities.

As a result, several techniques have been developed to control CAR T cell activation. The co-expression of a protease (NS3 from the hepatitis C virus) and a CAR that has been designed with an NS3 cognate cutting site in one novel approach allows CAR T cells to typically remain completely silenced.

Although proteolytic cleavage is prevented by the addition of an NS3 protease inhibitor, fully functioning CAR signaling and CAR T cell activation are still possible.

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.

Crystal Mackall MD, Director, Stanford Center for Cancer Cell Therapy

In an in vivo toxicity model,6 the Signal Neutralization by an Inhibitable Protease (SNIP)-CAR T cells exhibit effective anti-tumor activity with better survival and less toxicity than standard CAR T cells. Transient intervals of resting provide improved potency in SNIP CAR T cells.

As stated by Mackall, “remote-controlled CARs provide an opportunity to increase potency and diminish toxicity.”

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

References

  1. Patel, U. et al. CAR T cell therapy in solid tumors: A review of current clinical trials. eJHaem (2022) doi:10.1002/jha2.356
  2. Titov, A. et al. Advancing CAR T-cell therapy for solid tumors: Lessons learned from lymphoma treatment. Cancers (2020) doi:10.3390/cancers12010125
  3. 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
  4. 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
  5. Pietrobon, V. et al. Improving car t-cell persistence. International Journal of Molecular Sciences (2021) doi:10.3390/ijms221910828
  6. 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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Last updated: Nov 16, 2022 at 11:39 AM

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