Overcoming Challenges for CD3-Bispecific Antibody Therapy in Solid Tumors

Abstract

Immunotherapy of cancer with CD3-bispecific antibodies is an approved therapeutic option for some hematological malignancies and is under clinical investigation for solid cancers. However, the treatment of solid tumors faces more pronounced hurdles, such as increased on-target off-tumor toxicities, sparse T-cell infiltration and impaired T-cell quality due to the presence of an immunosuppressive tumor microenvironment, which affect the safety and limit efficacy of CD3-bispecific antibody therapy. In this review, we provide a brief status update of the CD3-bispecific antibody therapy field and identify intrinsic hurdles in solid cancers. Furthermore, we describe potential combinatorial approaches to overcome these challenges in order to generate selective and more effective responses.

Keywords: CD3-bispecific antibody; T-cell co-stimulation; T-cell engager; antibody therapy; immuno-oncology; on-target off-tumor toxicity; solid tumors; tumor-associated antigens.

Scheme 1

Explanation about T cell development and trafficking [82,83,84,85,86,87,88].

Figure 1

Three main hurdles for CD3-BsAb therapy in solid tumors. (1) CD3-BsAbs can generate on-target off-tumor toxicities by binding with the TAA arm to the same antigen on healthy cells, thereby redirecting T cells towards normal tissues, resulting in permanent tissue destruction. (2) Certain types of solid tumors (“immune desert” and “immune-excluded”) have sparse or even no T-cell infiltration, thereby preventing CD3-BsAb from cross-linking T cells to tumor cells, resulting in limited treatment efficacy. (3) The tumor microenvironment (TME) of solid tumors contains multiple immunosuppressive cell types, including cancer-associated fibroblasts, regulatory T cells and tumor-associated macrophages, thereby hampering the quality of effector T cells. Furthermore, immune checkpoints further decrease tumor-infiltrating lymphocyte (TIL) effector functions.

Figure 2

Solutions to mitigate hurdle 1: on-target off-tumor toxicities. (1) Target TAAs that are exclusively expressed by tumor cells, such as human leukocyte antigen (HLA)-presented neo-antigens, or surface antigens from virally induced cancers. (2) The avidity for TAAs can be increased with formats that include multiple TAA binding arms. This results in increased selectivity for tumor targeting over healthy tissues. (3) Binding arms of CD3-BsAbs can be masked using a protease-cleavable linker, making the BsAb only active inside the tumor. In healthy tissues, a minimal presence of proteases limits unmasking of the CD3 arm, whereas the abundance of matrix metallopeptidases (MMPs) in the TME allows the CD3-BsAb to redirect T cells towards the tumor. (4) Ensure local delivery of CD3-BsAbs to decrease systemic exposure by either local injection, or using delivery systems that locally produce these BsAbs, such as oncolytic viruses (OVs) and STAb-T cells.

Figure 3

Solutions for hurdle 2: sparse T-cell infiltration. (1) Pre-treatment with OV generates a strong interferon response in the tumor, resulting in local innate and adaptive immune responses and strong T-cell infiltration. (2) Disruption of the physical extracellular matrix (ECM) barrier prevents T cells from getting stuck in the ECM and allows infiltration into the tumor nests. (3) Targeting cancer-associated fibroblasts (CAFs) removes the major producers of ECM components and immune-excluding cytokines, thereby improving T-cell infiltration. (4) Blockade of immune-excluding cytokines reduces limiting factors for T-cell infiltration, resulting in better infiltrated tumors.

Figure 4

Solutions for hurdle 3: impaired TIL quality. (1) Targeting immunosuppressive cells such as CAFs, T_regs and tumor-associated macrophages (TAMs) depletes producers of immunosuppressive cytokines, thereby decreasing suppressive signals for T cells, improving their effector functions. (2) Direct blockade of immunosuppressive cytokines, instead of targeting their cellular producers, is able to achieve the same. (3) Addition of costimulation provides positive signals for T-cell effector functions and survival. (4) Providing sustaining cytokines can also improve T-cell functioning. (5) Blockade of immune checkpoints can prevent T-cell dysfunction and allow stronger anti-tumor responses.