Effect of local therapy on the systemic anti-tumor response in prostate cancer.

Abstract

243 Background: The genomic complexities and adaptability of aggressive cancer implies that it may only be eradicated by equally adaptable systems. Immune checkpoint blockade (such as that targeting PD−1 or CTLA−4) has shown dramatic and durable efficacy in immunogenic malignancies, but little or no benefit in less immunogenic cancers such as prostate cancer. Here we use a mouse model of prostate cancer to investigate whether local therapy can mount or augment an immune response to distant tumors. Methods: Immuno−competent FVB mice were bilaterally implanted with Myc−CAP cells to form isogenic grafts. Two weeks after tumor introduction, ablative therapies including radiation (stereotactically as a single 10 Gy fraction), cryoablation (two freeze−thaw cycles of less than −40 degree Celsius), whole tumor cauterization, or excision were applied to the larger graft in the presence of checkpoint blockade (intra−peritoneal anti−CTLA−4 or anti−PD1) or control injection (hamster anti−mouse IgG). Tumor sizes and mouse survival was recorded as was lymphocytic infiltrates which were characterized histologically and by flow cytometry. Results: Ablative therapies of cautery or cryoablation, but not excision or radiation caused a statistically significant delay in the growth of distant untreated tumors (P < 0.05 for both). Flow cytometric analysis demonstrated concurrent increases in the CD8+IFNgamma+ T cell population in the lymph nodes draining the untreated distant tumor. Flow also demonstrated an increase in CD4+FoxP3+ cells (P < 0.05 for each). Low dose anti−CTLA−4 therapy (1mg/kg) synergized with all local therapies to greatly increase survival and delay distant untreated tumor growth. This corresponded to an increase in activated T cells within distant tumors. Anti−PD−1 therapy did not synergize with local therapies. Conclusions: Some ablative local therapies (cautery, cryoablation) alone may incite an immune response in distant tumors. Checkpoint inhibition with low dose CTLA−4 blockade synergizes with all local therapies to incite a systemic anti−tumor response. PD−1 blockade has minimal effectiveness when combined with local therapies and may require combinatorial drug use for effectiveness in prostate cancer.