Abscopal Effect for Prostate Cancer? Does This Really Hold Promise?

The “abscopal effect” in cancer is frequently discussed, although very rarely seen.  While the term is used quite loosely, it technically is a situation where an untreated metastatic tumor will shrink concurrently while another site is undergoing a localized treatment.  Most commonly, radiation therapy is referenced as that local treatment.  Although the exact mechanism is unknown, it is postulated that the immune system is responsible for such an effect.1

Local irradiation of a tumor causes local tumor cell death through induction of double-strand DNA breaks, liberating unique tumor cell-specific antigen.2  These antigens can then be recognized and processed by antigen-presenting cells, components of the innate immune system.  These often include dendritic cells and macrophages that are in the tumor microenvironment.  These antigen-presenting cells can present the antigen to components of the adaptive immune system.  These are generally lymphocytes that are effectively “primed” to subsequently differentiate into effector cells that are capable of inducing cytotoxicity towards antigen-expressing tumor cells.  In essence, the “abscopal effect” relies upon this process to hypothesize that primed cytotoxic T cells are circulating through the blood stream to destroy tumor cells in a distant part of the body that was not receiving radiation.

The above explanation seems simple, but there is much pre-clinical evidence involving the cancer-immunity cycle that can further support the theory behind the “abscopal effect.”  For instance, radiation can promote this process through stimulation of calreticulin, a calcium-binding protein that promotes phagocytosis.Phagocytosis is further facilitated by the effects of radiation to downregulate CD47, a protein that decreases phagocytosis.4  MHC Class I expression can be increased with high doses of radiation, and that can increase potential for priming.Moderate doses of radiation can leave cytoplasmic DNA fragments and trigger the cGAS-STING pathway, which subsequently activates a type I interferon response in tumor cells.6, 7

While this all seems promising, clinical reports of the “abscopal response” are still rare and seem to occur more frequently in tumors such as metastatic melanoma.It is felt that in the majority of situations, the potential “abscopal effect” of ionizing radiation is blocked by the immunosuppressive microenvironment within the irradiated tumor, preventing effective T cell priming.  Hence, radiation alone is not generally sufficient, but the modern clinical use of checkpoint inhibitors may significantly increase the potential for the “abscopal effect” when combined with radiation therapy.9

In the realm of prostate cancer, we have a couple of potential hints from clinical trials that radiation therapy in combination with a checkpoint inhibitor may offer some benefit.  A chemotherapy pre-treated population of men with metastatic castration-resistant prostate cancer who received ipilumumab after radiation to a metastasis compared to placebo, just failed to reach statistical significance with a HR 0.85, 95% CI 0.72-1.00; p=0.053 in a randomized phase 3 trial.10  Interestingly, a pre-chemotherapy phase 3 trial with ipilumumab vs. placebo for men with metastatic castration-resistant prostate cancer, had no inkling of potential benefit (p=0.3667).11  One differentiating fact between the two trials is that the post-chemotherapy trial incorporated radiation prior to ipilumumab, whereas, the pre-chemotherapy trial had no radiation.  A phase 2 trial of patients with oligometastatic hormone-sensitive prostate cancer randomized patients to either radiation to a metastatic site followed by sipuleucel-T vs. sipuleucel-T alone.  Although median progression-free survival was in favor of the radiotherapy arm (3.52 vs. 2.46 months, p=0.06), statistical significance was not met.  Immune biomarkers to evaluate the cellular and humoral immune responses were not significantly different either.

With multiple trials of PD-(L)1 antibody therapy yielding limited efficacy in prostate cancer,12-15 it seems logical to combine these agents with radiation therapy to assess for synergistic or additive properties.  Although the dramatic “abscopal effect” may not be fully observed, the possibility of modest benefit exists with this type of combination, and clinical trial efforts are ongoing.  Below, I highlight multiple such ongoing immune-oncology with radiation therapy trials that span a broad spectrum of prostate cancer disease states.

                 

 

Select trials with immune-oncology and radiation therapy for prostate cancer patients (listed in order of earlier to later disease states)

  1. TALON - Neoadjuvant pembrolizumab, stereotactic body radiation and short term androgen deprivation therapy followed by radical prostatectomy for unfavorable risk localized prostate cancer (NCT04569461)
  2. Nivolumab with high dose rate brachytherapy, external beam radiation therapy and androgen deprivation therapy for Grade Group 5 localized prostate cancer (NCT03543189)
  3. Pembro-SRT – Salvage radiation therapy with pembrolizumab (NCT04931979)
  4. POSTCARD – stereotactic body radiation therapy with durvalumab for oligometastatic hormone-sensitive prostate cancer
  5. Pembrolizumab with stereotactic body radiation therapy with or without intratumoral SD-101 (TLR9 agonist) for new oligometastatic hormone-sensitive prostate cancer (NCT03007732)
  6. Androgen deprivation therapy, abiraterone acetate, stereotactic body radiation therapy to prostate and atezolizumab for new metastatic hormone-sensitive prostate cancer (NCT04262154)
  7. PORTER – Nivolumab, stereotactic body radiation therapy, CDX-301 (Flt3 inhibitor) and Poly-ICLC (toll like receptor-3 ligand) for metastatic castration-resistant prostate cancer (NCT03835533)
  8. Avelumab with PF-04518600 (Anti-OX40 antibody), utomilumab (41BB antibody) and radiation therapy for metastatic castration-resistant prostate cancer (NCT03217747)
Written by: Evan Yu, MD, Professor, Department of Medicine, Division of Oncology, University of Washington School of Medicine, Member, Clinical Research Division, Fred Hutchinson Cancer Research Center, Clinical Research Director, Genitourinary Oncology, Seattle Cancer Care Alliance, Medical Director, Clinical Research Service, Fred Hutchinson Cancer Research Consortium, Seattle, Washington

References

  1. Demaria S, et al. Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated. Int J Radiat Oncol Biol Phys 2004; 58:862-70.
  2. Ukleja J, et al. Immunotherapy Combined With Radiation Therapy for Genitourinary Malignancies. Front Oncol 2021; 11:663852.
  3. Obeid M, et al. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat Med 2007; 13:54-61.
  4. Vermeer DW, et al. Radiation-induced loss of cell surface CD47 enhances immune-mediated clearance of human papillomavirus-positive cancer Int J Cancer 2013; 133:120-9.
  5. Reits EA, et al. Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy. J Exp Med 2006; 203:1259-71.
  6. Harding SM, et al. Mitotic progression following DNA damage enables pattern recognition within micronuclei. Nature 2017; 548:466-70.
  7. Watson RO, et al. Extracellular M. tuberculosis DNA targets bacteria for autophagy by activating the host DNA-sensing pathway. Cell 2012; 150:803-15.
  8. Postow MA, et al. Immunologic Correlates of the Abscopal Effect in a Patient with Melanoma. N Engl J Med 2012; 366:925-31.
  9. Dewan MZ, et al. Fractionated but Not Single-Dose Radiotherapy Induces an Immune-Mediated Abscopal Effect when Combined with Anti–CTLA-4 Antibody. Clin Cancer Res 2009; 15:5379-88.
  10. Kwon ED, et al. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol 2014; 15:700-12.
  11. Beer TM, et al. Randomized, Double-Blind, Phase III Trial of Ipilimumab Versus Placebo in Asymptomatic or Minimally Symptomatic Patients With Metastatic Chemotherapy-Naive Castration-Resistant Prostate Cancer. J Clin Oncol 2017; 35:40-7.
  12. Topalian SL, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012; 366:2443-54.
  13. Fakhrejahani F, et al. J Clin Oncol 2017; 35(18 Suppl):5037a.
  14. Antonarakis ES, et al. Pembrolizumab for Treatment-Refractory Metastatic Castration-Resistant Prostate Cancer: Multicohort, Open-Label Phase II KEYNOTE-199 Study. J Clin Oncol 2020; 38:395-405.
  15. Sweeney CS, et al. Cancer Res (2020); 80 (16 Suppl):CT014a.
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