Mouse Models Provide Insight into Factors Affecting BiTE Efficacy

Although some cancers respond to immune checkpoint blockade (ICB), most patients do not see benefit from these drugs, and poor responses are typically associated with immunologically “cold” tumors. Another immunotherapy approach entails use of bispecific T cell engager (BiTE) therapies that link a single-chain variable domain (scFv) fragment targeting a tumor-associated antigen to an scFv targeting the CD3ϵ chain of the T cell receptor (TCR) and recruit polyclonal T cells to lyse tumor cells. BiTE molecules have shown promising preliminary results in some cancers, but the key biological variables which determine response to BiTE therapies are currently poorly understood. Using an immunocompetent mouse model expressing humanized CD3ϵ, Belmontes, Sawant, and colleagues tested 3 BiTE molecules directed at mouse CD19 or CLDN18.2 or human EPCAM in multiple syngeneic solid tumors to assess pharmacologic and immune parameters associated with BiTE efficacy. BiTE antitumor activity quantified by tumor volume was dose-dependent irrespective of the target protein, although sensitivity to BiTE therapy was different between syngeneic models, with response associated with baseline inflammation. BiTE molecules promoted T-cell proliferation and activation irrespective of whether tumors were sensitive or refractory to the therapy. Using bone marrow reconstitution, the authors were able to adjust the T-cell composition of syngeneic tumors, revealing that only a fourfold difference in T-cell density conferred resistance to BiTE molecules in previously responsive tumors. Combining BiTE molecules with antibodies targeting PD-1, CTLA4, or 4-1BB substantially increased antitumor activity in models unresponsive to either BiTE or ICB monotherapy. A pancreatic tumor model with low immunogenicity and T-cell density showed minimal response to BiTE molecules or ICB alone, but combination therapy induced a potent antitumor response, dependent on local expansion of tumor-associated CD8⁺ T cells. This study identified biological factors which influence the response to BiTE therapies and suggest that ICB, T-cell co-stimulation, and BiTE therapies, lacking efficacy on their own in immunologically cold tumors, could be successfully combined to induce profound antitumor responses.

Belmontes B, Sawant DV, Zhong W, Tan H, Kaul A, Aeffner F, et al. Immunotherapy combinations overcome resistance to bispecific T cell engager treatment in T cell–cold solid tumors. Sci Transl Med 2021;13:eabd1524.

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