Resistance Mechanisms to CAR T-Cell Therapy and Overcoming Strategy in B-Cell Hematologic Malignancies

Abstract

Chimeric antigen receptor (CAR) T-cell therapy has shown promising clinical impact against hematologic malignancies. CD19 is a marker on the surface of normal B cells as well as most B-cell malignancies, and thus has a role as an effective target for CAR T-cell therapy. In numerous clinical data, successes with cell therapy have provided anticancer therapy as a potential therapeutic option for patients who are resistant to standard chemotherapies. However, recent growing evidence showed the limitations of the treatment such as antigen-positive relapse due to poor CAR T-cell persistence and antigen-negative relapses associated with CAR-driven mutations, alternative splicing, epitope masking, low antigen density, and lineage switching. The understanding of the resistance mechanisms to the cell therapy has developed novel potential treatment strategies, including dual-targeting therapy (dual and tandem CAR), and armored and universal CAR T-cell therapies. In this review, we provide an overview of resistance mechanisms to CD19 CAR T-cell therapy in B-cell malignancies and also review therapeutic strategies to overcome these resistances.

Cellular immunotherapies for cancer

“…Antigen-positive relapse occurs due to inadequate cell persistence in the body, allowing the tumour to simply regrow and recover. Persistence of transferred cells is governed by intrinsic factors of the cell such as the quality, age, and presence of co-stimulatory domains in the setting of CAR-T/NK cells [4].…”

“…There are many ways that malignant cells can avoid identification and erasure by the host defence system; these include selection of tumour variants that have a nonimmunogenic phenotype, which occurs via a process known as immunoediting. This can manifest as downregulation of tumour antigen expression, creation of alternative versions of an antigen via mutations or alternative splicing, or masking of tumour antigens [4]. In addition to this, the creation of a hostile and immunosuppressive tumour microenvironment (TME) is a crucial tool for transformed cells to escape the immune response.…”

Improving the therapeutic index in adoptive cell therapy: key factors that impact efficacy

“…43 Bi-specific CARs with two extracellular binding motifs sharing the same intracellular signaling have been tested in hematologic malignancies. 44 Multiple antigens can also be targeted by universal CARs directed toward a soluble antigen-binding adaptor. 45 It is not clear, however, whether dual targeting may increase chances of on-target/off-tumor toxicity affecting benign tissues expressing either antigen.…”

“… 43 Bi-specific CARs with two extracellular binding motifs sharing the same intracellular signaling have been tested in hematologic malignancies. 44 Multiple antigens can also be targeted by universal CARs directed toward a soluble antigen-binding adaptor. 45 …”

Overcoming target epitope masking resistance that can occur on low-antigen-expresser AML blasts after IL-1RAP chimeric antigen receptor T cell therapy using the inducible caspase 9 suicide gene safety switch

“…There are various ways to overcome antigen escape and avoid failure in CAR T cell immunotherapy [15], such as improving CAR T cell production (using interleukin (IL)-7 and IL-15 rather than IL-2), combining the therapy with anti-checkpoint inhibitor antibodies, targeting an alternative cell surface epitope (i.e., CD20, CD22, etc.) expressed by the same tumor cells using dual-or tandem-specificity CARs [16], using a universal CAR [17], or armoring the CAR construct to enhance its antitumor activity [18].…”