Effect of combined anti-PD-1 and temozolomide therapy in glioblastoma

Abstract

Background: Although programmed death-1 (PD-1) blockade is effective in treating several types of cancer, the efficacy of this agent in glioblastoma (GBM) is largely unknown. Methods: We evaluated therapeutic effects of anti-PD-1, temozolomide (TMZ), and their combination in an orthotopic murine GBM model. The phenotype, number, and composition of lymphocytes were evaluated using flow cytometry. Transcriptional profiles of tumor tissues were analyzed using microarrays. Generation of antitumor immunological memory was investigated upon rechallenge. Results: Combined treatment with anti-PD-1 and TMZ yielded synergistic antitumor efficacy in the presence of donor-originated PD-1 + CD8 + T cells in vitro, necessitating in vivo validation. Whereas TMZ did not rescue GBM-implanted mice, anti-PD-1 completely eradicated GBM in 44.4% of mice, and combination of anti-PD-1 and TMZ in all mice. Anti-PD-1 significantly increased the number of tumorinfiltrating lymhpocytes (TILs), and reduced frequencies of exhausted T cells and regulatory T cells. However, combining TMZ with anti-PD-1 significantly decreased the number of TILs, which was also observed with TMZ treatment alone. A transcriptome analysis of tumor tissues revealed that anti-PD-1 monotherapy perturbed immune-related genes, distinctly with combined therapy. Upon rechallenge, tumor growth was not observed in mice cured by anti-PD-1 monotherapy, whereas tumors regrew in the combination group. Furthermore, an analysis of peripheral blood revealed that antitumor memory T cells were generated in mice cured by anti-PD-1 monotherapy, not in the combination group. Conclusion: PD-1 blockade induces long-term therapeutic response, and combination with TMZ further enhances antitumor efficacy. However, immunological memory is provoked by anti-PD-1 monotherapy, not by combined therapy. ARTICLE HISTORY

T lymphocyte-targeted immune checkpoint modulation in glioma

“…66 Combining anti-PD-1 with temozolomide, the standard of care for treatment of GBM, produces decreased tumor growth, increased TILs and improved survival when compared with monotherapy. [67][68][69] PD-1 blockade combined with oncolytic viral therapy has also been shown to increase survival in mice. 70 71 DC vaccines in combination with PD-1 inhibitors likewise demonstrate improved murine survival.…”

Case Report: A Case of Pituitary Carcinoma Treated With Sequential Dual Immunotherapy and Vascular Endothelial Growth Factor Inhibition Therapy

“…Although there is no similar clinical data for pituitary tumors, pre-clinical studies in murine glioblastoma models suggest that TMZ may impair response to immune checkpoint blockade. TMZ causes systemic immunosuppression, depletion of tumor infiltrating lymphocytes and inhibits JAK/STAT pathway signaling which decreases PD-L1 expression and may limit the effect of PD-1/ PD-L1 checkpoint inhibitors in the treatment of these tumors (59)(60)(61). In murine glioblastoma models, systemic TMZ was inferior to locally administered TMZ in combination with anti-PD-1 due to the immunosuppressive effects of systemic TMZ (60).…”

Inflammasome Sensor NLRP1 Confers Acquired Drug Resistance to Temozolomide in Human Melanoma

“…Accordingly, a combination strategy has been tried to improve the outcome, such as using chemotherapy and targeted therapies to increase tumor-specific antigen release and presentation [56]. So far, the combination of checkpoint blockade and TMZ therapy has yielded a promising anti-tumor efficacy in experimental models and clinical trials [57,58]. However, unlike vemurafenib, which reduces tumor-associated inflammation [50], TMZ not only enhances inflammatory response as observed in our current study but also promotes immune escape by upregulating PD-L1/L2 expression and reducing lymphocyte infiltration [57,59], thus potentially favoring a therapeutic response to immunotherapy [60].…”