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A preparation of autologous T-lymphocytes that express a chimeric antigen receptor (CAR) for the human epidermal growth factor receptor 2 (EGFR2; HER2; HER-2) and a dual-switch composed of chemical inducer of dimerization (CID)-inducible co-activation domain MyD88/CD40 (inducible MC; iMC), in which both the MyD88 and CD40 lack their extracellular domains, and an inducible caspase 9 (iCasp9) safety switch (CaspaCIDe), consisting of the CID-binding domain coupled to the signaling domain of caspase-9, with potential immunomodulating and antineoplastic activities. Upon administration of autologous HER2-targeted dual-switch CAR-T cells BPX-603, the T-cells target and bind to HER2-expressing cancer cells. Upon subsequent administration of the CID agent rimiducid (AP1903), this agent targets and binds to the drug binding domain of iMC and activates iMC, which leads to the activation of both CD40- and MyD88-mediated signal transduction pathways. This allows for enhanced T-cell proliferation, persistence and resistance to T-cell exhaustion and upregulation of immunomodulatory cytokines within the tumor microenvironment (TME). This increases the anti-tumor activity of the administered T-cells, compared to T-cells without the iMC activation-switch. As these T-cells are engineered to only be fully activated by binding to both the HER2 antigen and rimiducid, T-cell proliferation, activity and toxicity can be controlled by adjusting the dose of rimiducid, thereby preventing uncontrolled T-cell activation which increases the safety of the administered T-cells. The binding of rimiducid to the CID binding domain of iCasp9 results in the cross-linking and dimerization of iCasp9, which causes its activation. This results in the induction of caspase-mediated apoptosis of the transduced cells and allows for the removal of inappropriately activated cells, thereby preventing toxicity of the administered cells. HER2, a tumor-associated antigen (TAA), plays a key role in tumor cell proliferation and tumor vascularization.
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