In the field: exploiting the untapped potential of immunogenic modulation by radiation in combination with immunotherapy for the treatment of cancer

Abstract

Radiation has long been the standard of care for many types of cancer. It is employed to locally eradicate tumor cells as well as alter tumor stroma with either curative or palliative intent. Radiation-induced cell damage is an immunologically active process in which danger signals are released that stimulate immune cells to phagocytose and present locally released tumor-associated antigens (TAAs). Recent studies have indicated that radiotherapy can also alter the phenotype of cancer cells that remain after treatment. These cells upregulate TAAs as well as markers, including major histocompatibility complex and costimulatory molecules, that make them much more immunostimulatory. As our understanding of the immunomodulatory effects of radiation has improved, interest in combining this type of therapy with immune-based therapies for the treatment of cancer has grown. Therapeutic cancer vaccines have been shown to initiate the dynamic process of host immune system activation, culminating in the recognition of host cancer cells as foreign. The environment created after radiotherapy can be exploited by active therapeutic cancer vaccines in order to achieve further, more robust immune system activation. This review highlights preclinical studies that have examined the alteration of the tumor microenvironment with regard to immunostimulatory molecules following different types of radiotherapy, including external beam radiation, radiolabeled monoclonal antibodies, bone-seeking radionuclides, and brachytherapy. We also emphasize how combination therapy with a cancer vaccine can exploit these changes to achieve improved therapeutic benefit. Lastly, we describe how these laboratory findings are translating into clinical benefit for patients undergoing combined radiotherapy and cancer vaccination.

Keywords: abscopal effect; cancer immunotherapy; cancer vaccine; radiation therapy.

FIGURE 1

Phenotypic and microenvironmental changes in tumors elicited by RT that can be exploited by immunotherapy (Hodge et al., 2008) Each of the potential mechanisms of RT-induced immunogenic modulation shown here is discussed further and referenced in the text.

FIGURE 2

Combination of single-dose or fractionated RT with vaccine therapy. Mice transgenic for CEA were implanted subcutaneously on day 0 with the MC38-CEA tumor cell line, then randomized to receive either no treatment, vaccine alone, EBRT alone, or the combination of vaccine and EBRT. The vaccine consisted of poxviral vectors expressing CEA and TRICOM (rF/V-CEA/TRICOM). All vaccines were coadministered with a poxviral vector expressing GM-CSF. RT was administered either as a single dose (8 Gy on day 14) or fractionated (2 Gy on days 11, 12, 13, and 14). Neither modality was effective alone, but the combination of vaccine with single-dose or fractionated RT was curative in 40 and 55% of mice, respectively. (Adapted from Chakraborty et al., 2004.)

FIGURE 3

Combination of a radiolabeled mAb with vaccine increased survival in tumor-bearing mice. Mice transgenic for CEA were implanted subcutaneously on day 0 with the MC38-CEA tumor cell line. A control group (open squares) received HBSS buffer only. A second group (closed squares) received a vaccine consisting of poxviral vectors expressing CEA and TRICOM (rV/F-CEA/TRICOM). All vaccines were coadministered with a poxviral vector expressing GM-CSF. A third group (open triangles) received RT consisting of 100 μCi yttrium-90-labeled anti-CEA mAb (Y-90-labeled COL-1) intravenously on day 14. A fourth group (closed circles) received the combination of vaccine plus radiolabeled mAb. Mice were monitored weekly for tumor size and survival. (Adapted from Chakraborty et al., 2008a.)