Novel and Cellular Therapies
With the rare exception of case reports of patients with tumors that harbor ALK fusions that are responsive to ALK inhibition, the genomic landscape of mesothelioma is difficult to target. The loss of tumor suppressor genes suggests that synthetic lethality or collateral lethality may be a more appropriate strategy than that of direct kinase inhibition of oncogenes used in other tumor types. To that end, poly (ADP-ribose) polymerase (PARP) inhibitors have been explored in mesothelioma. One investigation that tested 10 mesothelioma cell lines that were characterized for BAP1 did not identify a correlation between BAP1 status and PARP inhibitor sensitivity. A clinical trial at the NIH suggested that the PARP inhibitor olaparib had minimal activity in MPM, and that patients with germline BAP1 mutations had worse outcomes than those who were wild-type for BAP1. By contrast, the Mesothelioma-Stratified Therapy study group just reported encouraging activity with the PARP inhibitor rucaparib in BAP1-deficient mesothelioma, suggesting that further investigation of this strategy is warranted.
In a similar fashion, Mesothelioma-Stratified Therapy also has an ongoing treatment arm with the CDK4/6 inhibitor abemaciclib for patients with tumors that lack p16 (which is encoded by CDKN2A). While these novel therapeutics are being explored in mesothelioma, BAP1 may affect the benefit with our current approved therapies. It was recently shown that patients with loss-of-function mutations in BAP1 or other DNA repair genes had improved overall survival with platinum-based therapy compared with patients whose tumors did not have these mutations.
Cellular therapies are also in development with both dendritic cells (DCs) and chimeric antigen receptor T cells (CAR-Ts). DCs are antigen-presenting cells that are critical to modulating immune responses against antigens. Upon collection and differentiation, DCs can be trained to promote an immunostimulatory response against selected antigens (Figure 3A). Although autologous DCs are used in most ongoing clinical trials, the choice of antigen sources differs widely: some use autologous tumor lysates, others use allogenic tumor lysates, and peptide loading, or transfection strategies are also possible. As genomic and bioinformatics approaches improve the identification of neoantigens, personalized vaccination strategies might become feasible with DCs.
Examples of cellular therapies. (A) In most clinical trials with dendritic cell vaccines, monocytes are removed by leukapheresis and matured, then loaded with tumor lysates or peptides, and administered to patients. (B) Similarly, to construct CAR-T cells, lymphocytes are isolated after leukapheresis and then undergo DNA or RNA transfection, or viral transduction, of a chimeric antigen receptor against a specific antigen, and are then administered. While the CAR-T cells are being created, patients typically undergo lymphodepletion to reduce immunosuppressive regulatory T cells. CAR-T, chimeric antigen receptor T cells; DC, dendritic cell. Used with permission of Mayo Foundation for Medical Education and Research, all rights reserved.
By contrast, most CAR-T trials that have included patients with mesothelioma have targeted the tumor-associated antigen mesothelin that is broadly expressed by epithelioid variants of mesothelioma. CAR-T cells are generated by DNA or RNA transfection, or viral transduction, of a chimeric antigen receptor that recognizes a specified antigen into T cells ex vivo (Figure 3B). CAR-T trials typically involve lymphodepletion before treatment to reduce immunosuppressive regulatory T cells and potentially improve the efficacy of the CAR-T cells. Most studies to date have demonstrated limited efficacy with poor infiltration of tumors, limited persistence of the CAR-T cells, and in some cases, anaphylactic reactions.[97,98] Hopefully, the humanization of the CAR-T constructs, expansion of targets, inclusion of suicide switches, combinations with immune checkpoint inhibitors, and other innovations will improve the therapeutic index with this approach. As our understanding of the vulnerabilities in mesothelioma improves, so will the therapeutic strategies we implement against it.
J Clin Oncol. 2022;40(6):681-692. © 2022 American Society of Clinical Oncology