Figure 1. Anti-BCMA TCE mechanism of... | American Society of Hematology

Figure 1.

$Anti-BCMA TCE mechanism of action and resistance. (A) TCEs redirect host T cells to enhance tumor killing by engaging CD3 on T cells and BCMA (or other target antigens) on MM cell surface. TCEs induce close-contact immune synapse and promote T-cell activation and granzyme and perforin release to target cells. (B) Distinct TCE molecular designs include those that feature monovalent vs bivalent BCMA binding domains as well as cis or trans orientation of CD3 and BCMA binding domains. (C) Mechanisms of MM resistance to TCE are broadly categorized into T-cell dysfunction, tumor intrinsic, and tumor microenvironment related features. Host T-cell dysfunction marked by the abundance of exhausted T cells (Tex), reduced effector T cells (Teff), expression of checkpoint molecules, and lack of clonotypic T-cell expansion contribute to primary refractoriness to TCE. Recruitment of regulatory T cells (Tregs) may also hinder TCE-mediated cytotoxic activity. Tumor intrinsic features leading to resistance include increased disease burden, R-ISS stage III, and extramedullary plasmacytoma. MM immune evasion occurs through mutation and/or deletions of BCMA or GPRC5D. Major histocompatibility complex I (MHCI) loss has also noted in some cases at relapse. MM cells release soluble BCMA into the TME, generating a ligand sink that attenuates TCE efficacy. The MM bone marrow milieu consists of immunosuppressive cells and cytokines. CTLA-4, cytotoxic T-lymphocyte associated protein 4; IDO, indoleamine 2,3-dioxygenase 1; IL, interleukin; LAG-3, lymphocyte activating 3; PD-1, programmed cell death protein 1; TGF-β, transforming growth factor-β; TIGIT, T-cell immunoreceptor with Ig and ITIM domains; TIM-3, T-cell immunoglobulin mucin 3; TOX, thymocyte selection associated high mobility group box.$

Anti-BCMA TCE mechanism of action and resistance. (A) TCEs redirect host T cells to enhance tumor killing by engaging CD3 on T cells and BCMA (or other target antigens) on MM cell surface. TCEs induce close-contact immune synapse and promote T-cell activation and granzyme and perforin release to target cells. (B) Distinct TCE molecular designs include those that feature monovalent vs bivalent BCMA binding domains as well as cis or trans orientation of CD3 and BCMA binding domains. (C) Mechanisms of MM resistance to TCE are broadly categorized into T-cell dysfunction, tumor intrinsic, and tumor microenvironment related features. Host T-cell dysfunction marked by the abundance of exhausted T cells (Tex), reduced effector T cells (Teff), expression of checkpoint molecules, and lack of clonotypic T-cell expansion contribute to primary refractoriness to TCE. Recruitment of regulatory T cells (Tregs) may also hinder TCE-mediated cytotoxic activity. Tumor intrinsic features leading to resistance include increased disease burden, R-ISS stage III, and extramedullary plasmacytoma. MM immune evasion occurs through mutation and/or deletions of BCMA or GPRC5D. Major histocompatibility complex I (MHCI) loss has also noted in some cases at relapse. MM cells release soluble BCMA into the TME, generating a ligand sink that attenuates TCE efficacy. The MM bone marrow milieu consists of immunosuppressive cells and cytokines. CTLA-4, cytotoxic T-lymphocyte associated protein 4; IDO, indoleamine 2,3-dioxygenase 1; IL, interleukin; LAG-3, lymphocyte activating 3; PD-1, programmed cell death protein 1; TGF-β, transforming growth factor-β; TIGIT, T-cell immunoreceptor with Ig and ITIM domains; TIM-3, T-cell immunoglobulin mucin 3; TOX, thymocyte selection associated high mobility group box.

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