Translating Combination Radiotherapy/Immunotherapy From Dogs to Humans With Advanced Melanoma or Sarcoma

Arta Monjazeb, MD

Michael Kent, DVM

With few exceptions, metastatic sarcomas and melanomas are incurable. At UC Davis Comprehensive Cancer Center, we have embarked on a novel study to improve these odds by combining radiotherapy and immune therapy. The research has shown good results so far in laboratory mice and promising results in a preliminary clinical trial of companion dogs with spontaneous tumors.

Patients with metastatic melanoma or with metastatic sarcoma are typically treated with chemotherapy, but with very limited success. Our approach harnesses the immune system to recognize the cancer and eliminate it as it would an infection.

Preliminary laboratory research in mice found that the immune therapy drug, a toll-like receptor agonist, is relatively ineffective against metastatic disease when given alone, but when combined with external-beam radiation therapy targeted to the primary tumor, the drug is effective systemically. Our study found that mice treated with both the drug and radiation therapy lived longer, the primary tumors shrunk significantly, and the rates of metastasis were significantly reduced. The tumors in the mice appeared to respond to an activation of the immune system.

We suspect that the radiation therapy plays a critical role in cancer cell death, first by causing local inflammation and changing the tumor vasculature to allow immune cells to infiltrate and home in on the cancer cells. We believe that the radiation treatment also kills the immunosuppressive cells in the tumor microenvironment, facilitating an immune response.

After in vitro studies verified that the immune therapy drug would work in dogs, we began a clinical trial of the combined approach in dogs being treated for advanced melanoma or sarcoma at the UC Davis Center for Companion Animal Health. The UC Davis Comprehensive Cancer Center, in partnership with the UC Davis School of Veterinary Medicine and their joint comparative oncology program, has several studies under way to find new treatments and better drug delivery systems that will benefit dogs with spontaneous tumors, and that may also lead to better therapies for human cancer patients.

Many cancers, including melanoma and sarcoma, behave very similarly in both dogs and humans, making dogs an excellent research model for these diseases. Use of laboratory mice with artificially implanted tumors for preclinical research is the subject of much criticism, as the mice models do not accurately represent human disease. We believe that companion canines who live in the same environment as their human owners and develop many of the same types of tumors spontaneously will serve as a better indication of which therapies will be effective in humans. This research will benefit both dogs and humans.

In this early phase trial, which began in the summer of 2012, dogs with advanced disease are given four treatments over 4 weeks. First, they receive a hypofractionated dose of radiation directed to the primary tumor site. Immediately after each treatment, we inject an immune-stimulating drug into the tumor. Theoretically, the radiation dose breaks up the tumor, and the immune-stimulating drug activates the immune system to recognize the tumor as foreign, eliciting an immune response.

The goal is for this treatment to act as a “vaccine” against the tumor. Combining immunotherapy with radiotherapy is designed to allow the dying tumor cells to effectively act as an in-situ vaccine, generating a systemic antitumor immune response.

The first drug activates the immune system and upregulates the presentation of tumor-associated antigens to the immune system. We then administer an additional drug that targets regulatory T cells to suppress the part of the immune system that keeps the body from recognizing the tumor. The second drug reverses tumor-induced immune suppression that would otherwise inhibit an antitumor immune response.

Essentially, we are using radiotherapy to debulk the tumor, release tumor antigens, and instigate an immune response. Then, we are using immunotherapy to “put one foot on the gas and remove the other foot from the brakes” of the immune system, allowing for a robust systemic immune response.

Arta Monjazeb, MD, discusses treatment plan with patient at the UC Davis Comprehensive Cancer Center.

Michael Kent, DVM, examines canine patient at the UC Davis Center for Companion Animal Health.

So far, the trial has demonstrated that radiation treatment of one site of the disease in dogs has caused a regression of distant metastases. We are monitoring all of the canine patients for response to the treatment. If we continue to see good results, we plan a larger trial in dogs. Ultimately, we hope to develop a clinical trial of the drug-radiation therapy combination in humans with melanoma, sarcoma, and other tumor types.