When the primary tumor in mice with either melanoma or pancreatic cancer was treated with radiation (RT) followed by an intratumoral injection of tumor-specific antibody fused with IL2 (IT-IC), Morris et al. surprisingly observed that the presence of a secondary, untreated tumor abrogated the therapeutic effect of RT+IT-IC on the primary tumor, an effect that was tumor-specific and partially due to Tregs. Adding IgG2a anti-CTLA-4 to the combination treatment reduced Tregs at the secondary tumor and increased CD8+ T cell infiltration in the primary tumor, leading to improved primary and secondary tumor control and increased survival.
In situ vaccination is an emerging cancer treatment strategy that uses local therapies to stimulate a systemic antitumor immune response. We previously reported an in situ vaccination effect when combining radiation (RT) with intra-tumor (IT) injection of tumor-specific immunocytokine (IC), a fusion of tumor-specific antibody and IL2 cytokine. In mice bearing two tumors, we initially hypothesized that delivering RT plus IT-IC to the "primary" tumor would induce a systemic antitumor response causing regression of the "secondary" tumor. To test this, mice bearing one or two syngeneic murine tumors of B78 melanoma and/or Panc02 pancreatic cancer were treated with combined external beam RT and IT-IC to the designated "primary" tumor only. Primary and secondary tumor response as well as animal survival were monitored. Immunohistochemistry and quantitative real-time PCR were used to quantify tumor infiltration with regulatory T cells (Tregs). Transgenic "DEREG" mice or IgG2a anti-CTLA-4 were used to transiently deplete tumor Tregs. Contrary to our initial hypothesis, we observed that the presence of an untreated secondary tumor antagonized the therapeutic effect of RT+IT-IC delivered to the primary tumor. We observed reciprocal tumor-specificity for this effect, which was circumvented if all tumors received RT or by transient depletion of Tregs. Primary tumor treatment with RT+IT-IC together with systemic administration of Treg-depleting anti-CTLA-4 resulted in a renewed in situ vaccination effect. Our findings show that untreated tumors can exert a tumor-specific, Treg-dependent, suppressive effect on the efficacy of in situ vaccination and demonstrate clinically viable approaches to overcome this effect.
Author Info: (1) Human Oncology, University of Wisconsin-Madison zmorris@humonc.wisc.edu. (2) Human Oncology, University of Wisconsin-Madison. (3) Human Oncology, University of Wisconsin-Madiso
Author Info: (1) Human Oncology, University of Wisconsin-Madison zmorris@humonc.wisc.edu. (2) Human Oncology, University of Wisconsin-Madison. (3) Human Oncology, University of Wisconsin-Madison. (4) Human Oncology, University of Wisconsin-Madison. (5) Human Oncology, University of Wisconsin-Madison. (6) Human Oncology, University of Wisconsin-Madison. (7) Human Oncology, University of Wisconsin-Madison. (8) Human Oncology, University of Wisconsin-Madison. (9) Human Oncology, University of Wisconsin-Madison. (10) Biostatistics, University of Wisconsin Carbone Cancer Center. (11) Apeiron Biologics. (12) Research, Provenance Biopharmaceuticals Corp. (13) Bristol Myers Squibb (United States). (14) Human Oncology, UW-Madison. (15) Human Oncology, University of Wisconsin-Madison. (16) Human Oncology, University of Wisconsin-Madison. (17) Human Oncology, University of Wisconsin-Madison. (18) Department of Pediatrics, University of Wisconsin School of Medicine and Public Health.
