Systemic Targeted Radionuclide Therapy Start PDF Download

New treatments are needed for metastatic prostate cancer. While patients initially respond to therapies that block the androgen receptor signaling which is required for prostate cancer growth, nearly all patients ultimately develop resistance to androgen deprivation therapy. Immune checkpoint blockade has been highly successful in treating many cancer types which have proved resistant to other lines of therapy, but these treatments have not been successful as monotherapies for prostate cancer. In contrast, the role of radiation therapy for treating prostate cancer has continued to expand. In addition to the long history of treating localized disease with external beam radiation therapy (EBRT), systemic radiation treatments that are able to deliver therapeutic doses to all sites of metastatic disease with relative sparing of healthy tissues have recently been approved. This systemic radiation modality is called targeted radionuclide therapy (TRT). It has been shown that EBRT is capable of sensitizing poorly immunogenic tumors to respond to immunotherapy through several activating effects on immune populations within the tumor. However, it is unknown whether TRT agents, which are more appropriate for widely metastatic disease, can elicit similar effects on the prostate tumor microenvironment and enhance the efficacy of immunotherapies. In particular, we focused on characterizing NM600, an alkylphosphocholine TRT agent which is taken up by several tumor types, including prostate cancer, and can be radiolabeled with multiple different radiometals. The overarching hypothesis of this work is that TRT, delivered via NM600, can remodel the prostate tumor microenvironment, rendering it susceptible to treatment with immunotherapy. We first evaluated the effects of 90Y-labeled NM600 alone on mouse prostate tumor allograft models. We found that 90Y-NM600 elicited a dose-dependent anti-tumor response but did not cause tumor regression even at the highest tolerated doses. Within 90Y-NM600-treated tumors, we observed an initial infiltration of activated, effector memory CD8+ T cells, but observed high PD-1 and PD-L1 expression over time. Based on these data, we investigated the effects of 90Y-NM600 together with PD-1 blockade. We found that this combination did not significantly improve anti-tumor efficacy due to the activating effects of PD-1 blockade on regulatory T cells. Next, we evaluated 90Y-NM600 in combination with tumor-specific vaccination. Specifically, we used a DNA vaccine encoding the ligand-binding domain of the androgen receptor which our lab has shown to elicit antigen-specific CD8+ T cell responses in both rodent models and in humans. We hypothesized that since we found that TRT could increase CD8+ T cell infiltration and promote an effector memory CD8+ T cell response, treatment with this vaccine would favor antigen-specific CD8+ T cell infiltration into the tumor following TRT administration. We found that the combination of single treatment TRT at the highest tolerated dose and vaccine did not improve anti-tumor efficacy despite a further initial increase in effector memory CD8+ T cells in the tumors of combination treated animals. However, two doses of TRT given three weeks apart in combination with vaccine did appear to improve anti-tumor efficacy possibly through decreasing PD-1 and PD-L1 signaling. We also observed that while 6 Gy of TRT and 6 Gy of EBRT were equally ineffective at improving anti-tumor response in combination with vaccine, increasing the dose of EBRT to 12 Gy did result in an additive anti-tumor response. Finally, we compared the effects of NM600 labeled with different radioisotopes, specifically the beta emitter 177Lu and the alpha emitter 225Ac, on our prostate tumor models. We found that 225Ac-NM600 treatment elicited a stronger anti-tumor effect than 177Lu-NM600. 225Ac-NM600 treatment also resulted in a bias towards activated, memory CD8+ T cells with sustained depletion of Tregs within the tumor. This suggests that 225Ac-NM600 may be the superior choice of radioisotope for combination with immunotherapy. Overall, these data demonstrate that the efficacy of TRT and immunotherapy combinations appear to be heavily dependent on the dose, fractionation, and type of radiation used, as well as specific effects of the chosen immunotherapy on cell types whose presence are promoted by the radiation. Further investigation into radiation and immunotherapy combinations are warranted due to the highly translatable nature of these findings.