Radiation and Cancer Biology

SS 43 - Biology 8 - Radiation and the Immune Response Session II

317 - Systemic Administration of Molecularly Targeted Radiation Therapy (MTRT) Improves the Efficacy of anti-CTLA-4 in a Murine B78 Melanoma Model

Wednesday, October 24
3:45 PM - 3:55 PM
Location: Room 004

Systemic Administration of Molecularly Targeted Radiation Therapy (MTRT) Improves the Efficacy of anti-CTLA-4 in a Murine B78 Melanoma Model
R. B. Patel1, R. Hernandez1, R. Brown1, J. Grudzinski1, P. Carlson1, R. N. Sriramaneni1, B. Bednarz1, P. M. Sondel2, J. Weichert1, and Z. S. Morris Jr3; 1University of Wisconsin, Madison, WI, 2University of Wisconsin School of Medicine and Public Health, Madison, WI, 3Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI

Purpose/Objective(s): External Beam Radiation (EBRT) has been used to sensitize a variety of cancers to standard immunotherapeutic treatment, however these effects are limited to a local site where EBRT can be safely delivered. Therefore, we designed a combination treatment approach utilizing anti-CTLA-4 in a preclinical B78 melanoma model together with a systemic injection of MTRT molecules, 90Y-NM600, to target all sites of disease with immunosensitizing radiotherapy. 90Y-NM600 is a radiolabeled alkylphosphocholine that has preferential uptake into tumors (confirmed by PET imaging in our tumor model).

Materials/Methods: C57BL/6 mice were subcutaneously injected with 2x106 B78 melanoma cells in the right flank. Once tumors grew to 80-90 mm3, they were randomized into the following treatment groups: PBS placebo, anti-CTLA-4 alone at 200 µg IP on days 4, 7, 10, and 90Y-NM600 IV on day 1 at doses of 25, 50, and 100 µCi w/wo anti-CTLA-4. Tumor measurements were made twice a week for 30 days, and survival was tracked to 60 days with a euthanasia endpoint for tumor burden. Mice with complete response (CR) to therapy were re-challenged with 2x106 B78 to the opposite flank 90 days after MTRT and then again at 120 days with Panc02 (murine pancreatic adenocarcinoma) and B16 melanoma to test for immune memory response. Additionally, a small pilot study with 8 animals compared EBRT (12 Gy to one tumor site) + anti-CTLA-4 w/wo MTRT in mice with bilateral ~200 mm3 tumors.

Results: The day 30 tumor sizes for the combination anti-CTLA-4 and MTRT (100, 50 µCi) were significantly decreased from all single agent or placebo groups p < 0.05 by ANOVA. Day 60 animal survival was 0% for PBS and MTRT alone groups and 33% for anti-CTLA-4 alone compared to 92% for combination MTRT and anti-CTLA4 at 50 and 100 µCi doses (p < 0.05 by log rank compared to control groups). 50% of the animals had a CR with the combination of 50 or 100 µCi MTRT with anti-CTLA-4 compared to 0% in the control or single agent treatment groups (p < 0.00001 by chi-square). All animals with CR had residual immune memory to B78 melanoma rechallenge with no tumor growth seen compared to naïve controls. All CR mice had immune memory to B16 melanoma as well but not to Panc02 challenge. Our pilot study of EBRT+ CTLA4 w/wo MTRT showed addition of MTRT significantly improved tumor growth delay in both primary and secondary tumors (p < 0.05) with 50% of mice having CR compared to 0% in the non-MTRT treated group.

Conclusion: Combination systemic MTRT with anti-CTLA-4 shows promising results in improving response rates to standard checkpoint blockade in our relatively immunologically “cold” B78 melanoma tumor model. While our primary study examined mice with a single flank tumor, all treatments were given systemically and could presumably have a similar effect at multiple sites of disease. This hypothesis was confirmed in our two tumor pilot study which showed improved response rates and abscopal effect to both primary and distant sites when MTRT was added to EBRT and checkpoint blockade.

Author Disclosure: R.B. Patel: None. R. Hernandez: None. R. Brown: None. J. Grudzinski: None. R.N. Sriramaneni: None. P.M. Sondel: None.

Ravi Patel, MD, PhD

Disclosure:
Employment
University Hospitals Case Medical Center: Resident Physician: Employee; University of Wisconsin: Clinical Instructor: Employee

Biography:
Dr. Ravi Patel, M.D. Ph.D., is a Bentson Radiation Oncology Research Fellow in the Department of Human Oncology at the University of Wisconsin. He received his MD and Ph.D. (in biomedical engineering) from Case Western University, and clinical residency training at the University Hospitals Cleveland Medical Center training program. Dr. Patel is an aspiring physician-scientist who is currently completing a research fellowship in the labs of Dr. Paul Sondel and Dr. Zachary Morris studying the interaction of radiaton and immunotherapy. In particular, Dr. Patel has developed a treatment regimen combining low dose molecularly targeted unsealed source radionuclides with systemic immune checkpoint inhibitors (ICI), such as anti-CTLA4 and anti-PD1, to improve their efficacy in immunologically "cold" tumors that normally have poor response to ICI alone. An exciting aspect about this type of immunotherapy treatment approach is that it could potentially improve patient outcomes for a variety of cancers. In addition to his Benston Research Fellowship Award, Dr. Patel has also received the Radiological Society of North America Fellow Research Award and the Amercican Society of Clinical Oncology Young Investigator Award to study this important research question.

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