An Odd But Synergistic Couple: Immunotherapy Combined With Radiotherapy

Radiation therapy (RT) and immunotherapy of cancer both date back more than 100 years, and yet, because radiation was often considered immunosuppressive, there had been little enthusiasm for combining them until recently. Immunotherapy has an established role in the treatment of some cancers-superficial bladder cancer treated with bacillus Calmette-Gurin (BCG), renal cell carcinoma and melanoma treated with interferon and interluekin (IL)-2 (Proleukin), and breast cancer and lymphoma treated with monoclonal antibodies such as trastuzumab (Herceptin) and rituximab (Rituxan), which partly function through antibody-dependent cellular cytotoxicity. Furthermore, radiation therapy and an antibody (cetuximab [Erbitux]) to the epidermal growth factor receptor have been shown to be efficacious in selected malignancies such as advanced head and neck cancer.[1]

However, widespread applicability of immunotherapy/radiotherapy combinations (especially with therapeutic vaccines) across most malignancies will require solutions to several challenges-in particular, the ability of tumors to evade or resist immune effectors and to invoke host regulatory mechanisms that limit the induction of high-frequency immune responses. Significant research efforts are now being applied to finding solutions to these challenges, and this has spawned numerous biotechnologies (new vaccine platforms, vaccine adjuvants, anti-CTLA4 antibodies, and recombinant cytokines) to enhance the effectiveness of cancer vaccines. Whether radiation therapy will be one of these solutions is, therefore, an important question.

Biologic Rationale

Hodge and colleagues[2] provide their rationale for combining radiation therapy with immunotherapy. In their review, they clearly define the biologic concepts that explain how these potentially paradoxical treatments might synergize for enhanced efficacy at not only the irradiated tumor site, but also at distant metastases. Specifically, radiation therapy causes upregulation or release of signals within a tumor that invoke dendritic cell migration to the tumor, phagocytosis of tumor cells, and maturation. These antigen-loaded dendritic cells migrate to regional lymph nodes and activate tumor antigen–specific T cells capable of tumor destruction.

In addition, radiation upregulates major histocompatibility complex (MHC)-peptide and immunomodulatory molecule expression on the tumor surface that may enhance the tumor cells’ susceptibility to T-cell recognition and attack. Finally, radiation therapy may eliminate regulatory immune cell populations that would otherwise hinder the development of effective antitumor T-cell responses.

In support of their model, the authors provide preclinical evidence and early clinical trial experience. However, while there is significant promise for combinations of immunotherapy and radiation therapy, there has been limited clinical trial experience thus far, and the eventual applicability of this approach is not known. We will therefore focus our editorial on issues to be considered in the further development of this strategy.

Optimizing Therapy and Patient Selection

The first issue is whether there is a preferred immunotherapy to combine with radiation. Hodge and coauthors mention nonspecific immunotherapies such as IL-2 and combinations with their poxvectors encoding the tumor antigen CEA. Others have reported combinations of radiation therapy with viral vectors encoding cytokines.[3] Given the limited data, it would appear that no one immunotherapy would be preferred.

The second issue is whether there is a preferred method of radiotherapy delivery to combine with immunotherapy. Hodge et al discuss external-beam treatment, radiopharmaceuticals, and radiolabeled monoclonal antibodies. All appear to synergize with immunotherapy. Although one might be concerned that delivery strategies resulting in persistent exposure to radioactivity at the tumor site would result in the death of T cells or dendritic cells attempting to infiltrate the site, in fact Hodge and colleagues report that tumor-infiltrating T cells and memory T cells are unaffected by radiotherapy.

The dose of radiation therapy will certainly be an important parameter to establish. The preclinical studies reviewed by Hodge and coauthors used doses as low as 8 Gy to as high as 80 Gy, whereas the clinical trials are using standard therapeutic doses of radiation therapy. Although there could be different effects on tumor cell expression of molecules that enhance immunogenicity, this is not established from any of the studies reviewed.

The timing of radiation therapy in relation to the immunotherapy is another critical issue. Utilizing a spontaneous prostate cancer (TRAMP) model, Harris[4] combined radiation therapy with adoptively transferred, prostate-specific CD4-positive T cells. The combination of immunotherapy with RT resulted in antitumor T-cell activation only when immunotherapy was administered 3 to 5 weeks post-RT. Immune responses were undetectable when immunotherapy was administered concurrently (periradiotherapy) or more than 5 weeks post-RT.

How this would translate into timing of radiation therapy for human tumors is not clear because of the different growth kinetics of human tumors as compared with murine tumors. Furthermore, this study used adoptively transferred T cells as a model for proof of principle, but human applications are more likely to use vaccines to stimulate T-cell responses. Thus, it would be important to determine when the tumor-specific T-cell response peaks after receiving the vaccine. Suckow[5] immunized rats with a prostate cancer vaccine 1 week before radiation therapy and demonstrated antitumor synergy.

Finally, the patient population that will benefit most from this strategy is not clear. Should this combination be considered in patients with advanced disease or in those with localized disease but with a high risk of distant metastases? Should the combination be used only in situations when radiation therapy is typically administered (such as the prostate cancer studies reported by Hodge and coauthors) or should the radiotherapy be applied specifically to enhance the immune response?

Conclusions

In summary, there is considerable promise for combinations of immunotherapy with radiotherapy, but clinical experience is still limited. Preclinical models with greater relevance to human tumors should be used to continue identifying the best combinations and timing of radiation therapy and immunotherapy, but of course, only clinical trials will establish the true value of these combinations. Because we are entering an era with numerous therapies for cancer, all of which might act synergistically, the importance of patient selection is paramount. Predictive factors that indicate which patients are most likely to benefit from immunotherapy or radiation therapy are critically needed.

Disclosures:

Financial Disclosure: Dr. Morse has received honoraria from Bristol-Myers Squibb and ImClone, and research support from Bristol-Myers Squibb.

References:

References

1. Bonner JA, Harari PM, Giralt J, et al: Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 354:567-578, 2006.
2. Hodge JW, Guha C, Neefjes J, et al: Synergizing radiation therapy and immunotherapy for curing incurable cancers: Opportunities and challenges. Oncology (Williston Park) 22:1064-1070, 2008.
3. Fujita T, Timme TL, Tabata K, et al: Cooperative effects of adenoviral vector-mediated interleukin 12 gene therapy with radiotherapy in a preclinical model of metastatic prostate cancer. Gene Ther 14:227-236, 2007.
4. Harris TJ, Hipkiss EL, Borzillary S, et al: Radiotherapy augments the immune response to prostate cancer in a time-dependent manner. Prostate June 16, 2008 (epub ahead of print).
5. Suckow MA, Wheeler J, Wolter WR, et al: Immunization with a tissue vaccine enhances the effect of irradiation on prostate tumors. In Vivo 22:171-177, 2008.