PSCA And MUC1 In Non-small-cell Lung Cancer As Targets Of Chimeric Antigen Receptor T Cells

Globally, lung cancer is the greatest killer among all cancers, and non-small-cell lung cancer (NSCLC) accounts for approximately 85% of all cases of lung cancer.Current therapeutic strategies, including surgery, radiation and chemotherapy, have not yielded significant survival benefits. Tyrosine kinase inhibitors (TKIs) targeting EGFR and ALK have been widely used to treat NSCLC, but frequent resistance to these drugs develops due to acquired mutations of EGFR and of ALK. Furthermore,recently introduced CTLA4, PD-1 and PD-L1 immune checkpoint inhibitors have had no or only moderate effects on NSCLC. Therefore, novel treatment regimens are still needed.Chimeric antigen receptor (CAR) T cells that target CD 19 have generated exciting results in leukemia and lymphoma. However, the broad applicability of these cells for solid cancer is limited by the paucity of truly tumor-specific target antigens.Additionally, the heterogeneity of tumor-associated antigens (TAAs) in solid cancers complicates CAR T cell therapies, as the targets may differ among various cancers and even patients of a same cancer. Therefore, it is important to define the TAA profile of a solid cancer before using TAA-oriented personalized CAR T cell immunotherapies.Few CAR T cell antigens have been targeted to treat NSCLC. Glypican-3 was recently reported as a promising target for lung squamous cell carcinoma. In a phase I clinical trial of anti-epidermal growth factor receptor (EGFR) CAR T cells for lung cancer, only 2 of 11 patients achieved partial responses. The expression of MUC1, a transmembrane glycoprotein, is aberrantly upregulated in many types of cancer,including NSCLC. A trial of MUC1-targeting CAR T cells is currently recruiting patients with four types of solid cancers, including NSCLC (ClinicalTrials.gov Identifier: NCT02587689). Hence, MUC1 is a promising CAR T cell target in NSCLC.Prostate stem cell antigen (PSCA) is a glycosylphosphoinositol-anchored cell surface antigen that is overexpressed mainly in prostate cancer, although its expression has also been reported in other tumors such as gallbladder adenocarcinomaand gastric cancer. Surprisingly, PSCA is frequently overexpressed in NSCLC, although this requires confirmation. Antibody-based, PSCA-targeted therapies, as well as a peptide vaccine, have been explored for the treatment of prostate cancer. Furthermore, PSCA-targeting CAR T cells have been used to treat pancreatic cancer in humanized mice, and clinical trials of anti-PSCA CAR T cells for the treatment of prostate, bladder and pancreatic cancers are ongoing(ClinicalTrials.gov Identifier, NCT02092948 and NCT02744287). It remains unknown, however, whether anti-PSCA CAR T cells could be used to treat NSCLC.Patient-derived xenograft (PDX) models have been widely used in translational cancer research, which faithfully resemble the original tumors from which they were developed and this similarity is maintained across passages. In this study,we generated patient-derived xenograft (PDX) mouse models of human NSCLC thatmaintained the antigenic profiles of primary tumors.Next, we demonstrated the expression of PSCA and MUC1 in NSCLC, followed by the generation and confirmation of the specificity and efficacy of PSCA- and MUC1-targeting CAR T cells against NSCLC cell lines in vitro.Finally, we demonstrated that PSCA-targeting CAR T cells could efficiently suppressNSCLC tumor growth in PDX mice and synergistically eliminate PSCA+MUC1+tumors when combined with MUC1-targeting CAR T cells. Taken together, our studies demonstrate that PSCA and MUC1 are both promising CAR T cell targets in NSCLC and that the combinatorial targeting of these antigens could further enhance the anti-tumor efficacy of CAR T cells.