Zachary S. Morris, MD, PhD
One of the hallmarks of tumorigenesis is the ability of cancer cells to suppress, or circumvent, the host immune system.1
Advances in strategies to overcome tumor cell evasion of immune detection have led to a rapid pace of preclinical and clinical development in the field of cancer immunotherapy. Most notably, in recent years T-cell checkpoint inhibitors have demonstrated therapeutic efficacy in multiple cancer types. This class of immunotherapy modulates tumor tolerance among T cells by antagonizing specific inhibitory receptor–ligand interactions, thereby enhancing T-cell activation.
A frequent observation from clinical studies of T-cell checkpoint inhibitors is that even in the context of metastatic disease, a small subgroup of patients who respond to treatment have complete and durable regression of disease. This raises the possibility that augmenting response rates to checkpoint blockade or other such immunotherapies may result in a dramatic impact on survival of patients with advanced-stage malignancy. Nevertheless, durable tumor response remains elusive for the overwhelming majority of patients with metastatic cancers, and immunotherapies are not typically effective in patients with immunologically “cold” tumors, characterized by low levels of T-cell infiltrate and few mutation-created neoantigens.
One potential approach to improving the response to cancer immunotherapies is to combine such treatments with radiotherapy (RT). Radiation may interact with the tumor immune microenvironment at a targeted site through various mechanisms, including: (1) temporary local eradication of radiation-sensitive immune lineages including suppressor and effector lymphocytes; (2) local release of inflammatory cytokines and damage-associated molecular patterns, resulting in local effects on endothelial cell expression of adhesion receptors, immune cell trafficking, and immune cell activation; (3) immunogenic tumor cell death and release of tumor-specific antigens; and (4) induction of phenotypic changes in the expression of immune susceptibility markers on tumor cells surviving radiation.2
Because of these effects, radiation may enhance antigen cross-presentation and diversification of antitumor T-cell responses.3,4
By modulating tumor immune tolerance and functional immunogenicity at a targeted site, external beam radiation therapy may serve as a method of in situ tumor vaccination, a therapeutic strategy that is intended to convert a patient’s own tumor into a nidus for presentation of tumor-specific antigens that will stimulate and diversify an antitumor T-cell response.5,6
The capacity of external beam radiation alone to elicit a systemic antitumor immune response is well documented (eg, abscopal effect) but quite rare.7
In the context of targeted immunotherapies such as checkpoint inhibitors, however, multiple preclinical studies have demonstrated that localized radiation therapy can consistently enhance a systemic antitumor immune response.4,8-10
Results from retrospective clinical studies indicate the safety of such combinations.11-14
This highlights decades of improvements in the physical targeting of radiation therapy and the molecular targeting of immunotherapies, which have rendered these treatments increasingly amenable to combined modality approaches (Figure
). However, prospective clinical studies reported to date have not demonstrated response rates greater than anticipated with checkpoint blockade alone.4,15-18
More than 100 ongoing clinical studies are now investigating combinations of radiation therapy with immune checkpoint inhibition in various clinical contexts. This unprecedented extent of clinical investigation reflects both the promise and enthusiasm for such approaches, as well as a degree of uncertainty about the circumstances, disease sites, radiation dose and fractionation, timing and sequencing, and clinical settings that may portend greatest benefit for immuno-RT combinations.
Figure. Historical Convergence of Radiotherapy and Immunotherapy Advancements
As we await the emergence of clinical data that might demonstrate a cooperative interaction between radiation and immunotherapies, next-generation approaches to augment such interactions are already entering early-phase clinical investigation. For example, based on promising preclinical data showing an enhanced in situ vaccine effect with the combination of external beam radiation and intratumoral injection of a tumor-specific immunocytokine (tumor-specific antibody fused to immune-stimulatory IL-2 cytokine),19
our melanoma research team at the University of Wisconsin is advancing a unique phase I/II clinical trial. This study (UW16134) will test the safety of intratumoral injection of APN301 (hu14.18–IL-2) immunocytokine (Apeiron Biologics) alone and together with local radiation therapy and systemic administration of single- or dual-agent checkpoint blockade (Bristol-Myers Squibb). The study will enroll patients with metastatic melanoma and is led by members of our melanoma clinical research team, including Paul Sondel, MD, PhD; Mark Albertini, MD; and Zachary Morris, MD, PhD. At the same time, this team is advancing preclinical investigations of novel strategies that may overcome potential limitations of in situ vaccine approaches.20
Notably, this includes collaborative studies—led by Jamey Weichert, PhD; Mario Otto, MD, PhD; and Bryan Bednarz, PhD—investigating the use of moleculartargeted radionuclide therapies (Archeus Ltd) that may enable delivery of immunomodulatory RT to all tumor sites in the setting of metastatic or multifocal disease. Our colleague Ravi Patel, MD, PhD, was scheduled to present early and very promising results of these studies in October 2018 at the American Society for Radiation Oncology Annual Meeting in San Antonio, Texas.
As the immuno-oncology revolution transforms clinical practice, tremendous opportunities continue to arise for leveraging combined modality approaches to improve antitumor immune response and patient outcomes. Ultimately, the successful development of such approaches and their incorporation into standard practice will depend on the advancement of well-conceived clinical studies founded on rigorous preclinical investigation. We look forward to partaking in this effort.
- Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646-674. doi: 10.1016/j.cell/2011.02.013.
- Demaria S, Bhardwaj N, McBride WH, Formenti SC. Combining radiotherapy and immunotherapy: a revived partnership. Int J Radiat Oncol Biol Phys. 2005;63(3):655-666. doi: 10.1016/j.ijrobp.2005.06.032.
- Sharabi AB, Nirschl CJ, Kochel CM, et al. Stereotactic radiation therapy augments antigen-specific PD-1-mediated antitumor immune responses via cross-presentation of tumor antigen. Cancer Immunol Res. 2015;3(4):345-355. doi: 10.1158/2326-6066.CIR-14-0196.
- Twyman-Saint VC, Rech AJ, Maity A, et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature. 2015;520(7547):373-377. doi: 10.1038/nature14292.
- Brody JD, Ai WZ, Czerwinski DK, et al. In situ vaccination with a TLR9 agonist induces systemic lymphoma regression: a phase I/II study. J Clin Oncol. 2010;28(28):4324-4332. doi: 10.1200/JCO.2010.28.9793.
- Marabelle A, Tselikas L, de Baere T, Houot R. Intratumoral immunotherapy: using the tumor as the remedy. Ann Oncol. 2017;28(suppl 12):xii33-xii43. doi: 10.1093/annoncmdx683.
- Abuodeh Y, Venkat P, and Kim S. Systematic review of case reports on the abscopal effect. Curr Probl Cancer. 2016;40(1):25-37. doi: 10.1016/j.currproblcancer.2015.10.001.
- Dewan MZ, Galloway AE, Kawashima N, 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(17):5379-5388. doi: 10.1158/1078-0432.CCR-09-0265.
- Demaria S, Kawashima N, Yang AM, et al. Immune-mediated inhibition of metastases after treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer. Clin Cancer Res. 2005;11(2 pt 1):728-734. clincancerres.aacrjournals.org/content/11/2/728.
- Verbrugge I, Hegkyriakou J, Sharp LL, et al. Radiotherapy increases the permissiveness of established mammary tumors to rejection by immunomodulatory antibodies. Cancer Res. 2012;72(13):3163-3174. doi: 10.1158/0008-5472.CAN-12-0210.
- Barker CA, Postow MA, Khan SA, et al. Concurrent radiotherapy and ipilimumab immunotherapy for patients with melanoma. Cancer Immunol Res. 2013;1(2):92-98. doi: 10.1158/2326-6066.CIR-13-0082.
- Chandra RA, Wilhite TJ, Balboni TA, et al. A systematic evaluation of abscopal responses following radiotherapy in patients with metastatic melanoma treated with ipilimumab. Oncoimmunology. 2015;4(11):e1046028. doi: 10.1080/2162402X.2015.1046028.
- Ahmed KA, Stallworth DG, Kim Y, et al. Clinical outcomes of melanoma brain metastases treated with stereotactic radiation and anti-PD-1 therapy. Ann Oncol. 2016;27(3):434-441. doi: 10.1093/annonc/mdv622.
- Bang A, Wilhite TJ, Pike LGR, et al. Multicenter evaluation of the tolerability of combined treatment with PD-1 and CTLA-4 immune checkpoint inhibitors and palliative radiation therapy. Int J Radiat Oncol Biol Phys. 2017;98(2):344-351. doi: 10.1016/j.ijrobp.2017.02.003.
- Kwon ED, Drake CG, Scher HI, et al; CA184-043 Investigators. 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(7):700-712. doi: 10.1016/S1470-2045(14)70189-5.
- Williams NL, Wuthrick EJ, Kim H, et al. Phase 1 study of ipilimumab combined with whole brain radiation therapy or radiosurgery for melanoma patients with brain metastases. Int J Radiat Oncol Biol Phys. 2017;99(1):22-30. doi: 10.1016/j.ijrobp.2017.05.028.
- Tang C, Welsh JW, de Groot P, et al. Ipilimumab with stereotactic ablative radiation therapy: phase I results and immunologic correlates from peripheral T cells. Clin Cancer Res. 2017;23(6):1388-1396. doi: 10.1158/1078-0432.CCR-16-1432.
- Hiniker SM, Reddy SA, Maecker HT, et al. A prospective clinical trial combining radiation therapy with systemic immunotherapy in metastatic melanoma. Int J Radiat Oncol Biol Phys. 2016;96(3):578-588. doi: 10.1016/j.ijrobp.2016.07.005.
- Morris ZS, Guy EI, Francis DM, et al. In situ tumor vaccination by combining local radiation and tumor-specific antibody or immunocytokine treatments. Cancer Res. 2016;76(13):3929-3941. doi: 10.1158/0008-5472.CAN-15-2644.
- Morris, ZS, Guy EI, Werner LR, et al. Tumor-specific inhibition of in situ vaccination by distant untreated tumor sites. Cancer Immunol Res. 2018;6(7):825-834. doi: 10.1158/2326-6066.CIR-17-0353.