Chemotherapeutic drugs and kinase inhibitors play important roles in clinical cancer treatment. In order to elicit stronger antitumor activity, some researchers are attempting to combine CAR T cell therapy with these drugs. Fraietta et al. [
22] found that T cells from chronic lymphocytic leukemia (CLL) patients usually exhibit deficiencies in proliferation, and this proliferative defect is completely reversed after long-term ibrutinib therapy. Ibrutinib is a first-in-class irreversible inhibitor of Bruton tyrosine kinase (BTK), which can irreversibly inhibit the IL-2 inducible T cell kinase (ITK). Ibrutinib inhibits Th2-polarized CD4 T cells, thus skewing T cells toward a Th1 anti-tumor immune response. Therefore, Fraietta et al. combined ibrutinib with CTL019 for treatment of CLL, and the results demonstrated that Ibrutinib increased the expansion of CTL019 and decreased PD-1 and CD200 expression from CLL patients ex vivo. Moreover, they found that continuous ibrutinib treatment could enhance CTL019 efficacy in drug-resistant ALL and CLL mouse models. Ruella et al. [
23] also added Ibrutinib to CTL019 for the treatment of mantle cell lymphoma; the results demonstrated that 80–100% of mice in the CTL019+ ibrutinib arm and 0–20% of mice in the CTL019 arm remained in long-term remission (p < 0.05). Prostaglandin E2 (PGE2) and adenosine are two other critical immunosuppressive mediators that are present in solid tumors. PGE2 and adenosine activate protein kinase A (PKA), which then inhibits T cell receptor (TCR) activation. This inhibition process requires PKA to localize to the immune synapse by binding to the membrane protein ezrin. Newick et al. [
24] manufactured anti-mesothelin CAR T cells that co-expressed a small peptide called the “regulatory subunit I anchoring disruptor” (RIAD). RIAD can prevent the association of PKA with ezrin, thus eliminating the negative effects of PKA on TCR activation. Lenalidomide is a synthetic derivative of thalidomide, which has multifaceted immunomodulatory efficacies. The most outstanding function of lenalidomide is to restore and facilitate immune synapse formation between T cells and antigen presenting cells. Kuramitsu et al. [
25] added lenalidomide to EGFRvIII (epidermal growth factor receptor variant III)-targeted CAR T cells against glioblastoma multiforme (GBM). An interesting and novel finding of their study was that lenalidomide enhanced immunological synapse formation between the effector cells and the target cells and then enhanced the persistent antitumor activity of CAR T cells. The interaction between HVEM (TNFRSF14) and BTLA (B and T lymphocyte attenuator) is lost in most follicular lymphomas due to an HVEM mutation. HVEM deficiency induces a tumor-supportive microenvironment. Boice et al. [
26] modified anti-CAD19 CAR T cells to become in vivo micro-pharmacies for the local delivery of soluble HVEM, and these modified CAR-T cells showed enhanced therapeutic activity against xenografted lymphomas.