For the past 50 years or more, oncologists have designed their treatment plans around the three pillars: surgery, chemotherapy, and radiation. Now, with a series of recent successes, immunotherapy is rapidly reemerging as the fourth pillar in the oncologic armamentarium. Despite major advancements in cancer therapeutics, metastatic disease remains a persistent clinical enigma, accounting for about 90% of all cancer-related deaths. However, promising reemerging and new research into a systemic immunologic response known as the abscopal effect might finally help researchers unlock the key to metastatic disease.

Promising Early Indications

R.H. MOLE, MD, coined the term “abscopal effect” in 1953 to describe “an action at a distance from the irradiated volume within the same organism.¹” The word abscopal is derived from Latin roots: ab- (position away from) and -scopos (a target for shooting at). In oncology, the abscopal effect describes the ability of localized radiation to initiate an antitumor response that kills cancer cells distant to the primary target. Researchers leading this rapidly progressing field postulate that accurately targeted radiotherapy in conjunction with immunotherapy could trigger an abscopal effect durable enough to control or eradicate metastatic cancer.

A 2015 proof-of-principle trial² was the first to demonstrate that abscopal responses could be consistently identified in patients with solid metastatic cancer that had been treated with radiation and immunotherapy. “The initial goal of the trial was to induce an abscopal response in patients with metastatic cancer,” said lead author Encouse B. Golden, MD, PhD, Assistant Professor of Radiation Oncology at the University of California, San Francisco. 

“Tolerable side effects were a positive finding, given the need for further research in [radioimmunotherapy to provoke an abscopal response], where the long-term goal is to develop an in situ antitumor vaccine.”

— Encouse B. Golden, MD, PhD

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“As our immune agent, we chose granulocyte-macrophage colony-stimulating factor (GM-CSF), as it’s a cytokine that activates dendritic cells, which are getting a lot of attention. Our aim was to combine radiotherapy with the colony-stimulating factor to see if it would result in abscopal responses among the patients on trial.”

Positive Responses

DR. GOLDEN, Dr. Silvia Formenti, and their collaborators enrolled 41 patients with stable or progressing metastatic tumors (at least 3 distinct sites of measurable disease) on standard systemic treatments. The patients were maintained on their previous standard regimens and received subcutaneous administration of GM-CSF. They also received fractionated radiation to 1 of their measurable tumors, after which the nonirradiated tumors were evaluated by physical exam or computed tomography scans about 7 weeks into the treatment. The researchers defined an abscopal response as a reduction of 30% or more in any measurable nonirradiated tumor.

The investigators found that 27% of the patients on the regimen had defined abscopal responses, indicating that treatment with GM-CSF and fractionated radiation, when combined with a systemic regimen, may activate an immune response that can overcome immune tolerance. “There were several different solid tumor sites on the trial, but the most well represented were non–small cell lung cancer (NSCLC) and breast cancer,” said Dr. Golden. “We saw four abscopal responses in patients with NSCLC and five in those with breast cancer.”

He added, “The adverse events were tolerable, mostly fatigue, which occurred in six patients. Tolerable side effects were a positive finding, given the need for further research in this area, where the long-term goal is to develop an in situ antitumor vaccine.”

Cryosurgery and the Abscopal Effect

CRYOSURGERY, IN various iterations, has been around for centuries, dating back to Napoleonic times. This therapeutic approach had a renaissance in the 1990s and is currently used in a wide variety of cancers, including liver metastases, breast adenomas, prostate, and brain tumors. Cryoablation kills cancer cells by removing the tumor’s heat and transferring it to surrounding tissues, thus creating an internal region of direct cell death by lethal hypothermia, while killing cells in the outer region by apoptotic signaling.

Beginning in the mid to late 1960s, a series of papers described cryosurgery-induced abscopal effects. Early observers noted how cryosurgery of the prostate released circulating antigens, referring to this phenomenon as cryoimmunization. In 1969, Richard J. Ablin, PhD, DSc (Hon), Dr. hc, now Professor of Pathology at The University of Arizona College of Medicine, Arizona Cancer Center, and BIO5 Institute, Tucson, and his associates Maurice J. Gonder, MD, and Ward A. Soanes, MD, published a case report of cryosurgery-induced abscopal responses in three patients with prostate cancer, citing regression of distant metastases in the cervical spine, lungs, and left supraclavicular lymph nodes following cryoablation of the primary prostate cancer.

Dr. Ablin described his early immunologic studies of the prostate at the Millard Fillmore Hospital in Buffalo, New York: “We froze the prostate and accessory sexual glands of reproduction of rats, monkeys, and dogs (with the exception of the seminal vesicles absent in dogs) with liquid nitrogen and discovered an immune response. We then took animals with bilateral tumors and froze one tumor, leaving the contralateral tumor untreated. The cryosurgery not only destroyed the treated tumor, but it set off a systemic effect also destroying the contralateral unfrozen tumor.”

“It became clear to me that the status of a patient’s immune system directly affected metastatic tumor shrinkage from the cryoimmune response.”

— Richard J. Ablin, PhD, DSc (Hon), Dr. hc

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Drs. Ablin, Gonder, and Soanes had seven patients with stage IV adenocarcinoma of the prostate. Based on the success of their animal work, the researchers froze the patients’ prostates with a probe inserted in the urethra, guiding it rectally with a finger until the tip was positioned on the prostate, and depressing a pedal released the liquid nitrogen on the target.

“When we froze the prostates a second and third time, we produced a ‘booster response’ similar to a vaccination. Our clinical observations of the patients treated cryosurgically for prostate cancer showed instances of partial or complete remission of metastatic lesions. We published our findings in International Surgery³ and The Journal of Urology.⁴ This was some of the pioneering work in eliciting the abscopal effect to treat metastatic disease,” said Dr. Ablin. “It became clear to me that the status of a patient’s immune system directly affected metastatic tumor shrinkage from the cryoimmune response, and he coined the term ‘cryoimmunotherapy.’”

A Radiation Oncologist’s Perspective

JOHN NG, MD, Assistant Professor of Radiation Oncology at Weill Cornell Medical College, has closely followed the accelerating research in combining radiotherapy with immunotherapy to trigger abscopal responses. Dr. Ng told The ASCO Post, “Oncologists are excited about the emergence of drugs that can activate the immune system to combat metastatic disease. One of the most promising modalities that can act synergistically with immunotherapy is radiation therapy. Perhaps with radiation releasing antigens in a patient primed for an immune response, a durable long-term protective effect similar to that of a vaccine can occur.”

“Perhaps with radiation releasing antigens in a patient primed for an immune response, a … protective effect similar to that of a vaccine can occur.”

— John Ng, MD

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Asked whether the radiation dose and delivery schedule affect different tumors differently, Dr. Ng, replied, “Tumor type, dose, and schedule all probably matter. There are exciting data from clinical trials showing that radiation or chemoradiation can work in combination with checkpoint blockade as an effective therapeutic strategy.” There is some elegant work by Silvia Chiara Formenti, MD; Sandra Demaria, MD; and others indicating that there may be a ‘sweet spot’ in terms of radiation dose. It may be what we consider an intermediate clinical radiation dose that best triggers the abscopal effect. As to timing, no one really knows, although the most popular strategy is probably delivering the radiation and immunotherapy agents concurrently.”

Dr. Ng noted that there are currently more than 100 clinical trials underway worldwide involving some combination of checkpoint blockade and radiation. “It’s probably the most popular concept being tested in combining radiation and immunotherapy. There are other agents being tested with radiation, including new checkpoint blockade drugs and T-cell, macrophage, dendritic cell, and innate immunity modulators among others. What is reassuring from the early results of these clinical trials is that the combination of radiotherapy and immunotherapy appears to be very well tolerated, without any markedly increased side effects compared with either modality alone.”

Conclusion

ALTHOUGH THE MECHANISM of the abscopal effect is not yet completely understood, the distant antitumor effects produced by combining cryotherapy, radiotherapy, and immunotherapy have been widely reported in preclinical and clinical studies. Previous and ongoing work in this promising field provides researchers with a solid platform of data to explore and build on. The potential to unleash a powerful immune response that eradicates cancer cells distal from the primary tumor could represent a giant leap forward in our knowledge of metastatic disease and how to treat it. ■

DISCLOSURE: Drs. Golden, Ablin, and Ng reported no conflicts of interest.

REFERENCES

1. Mole RH: Whole body irradiation: Radiobiology or medicine? Br J Radiol 26:234-241, 1953.

2. Golden EB, Chhabra A, Chachoua A, et al: Local radiotherapy and granulocyte-macrophage colony-stimulating factor to generate abscopal responses in patients with metastatic solid tumours: A proof-of-principle trial. Lancet Oncol 16:795-803, 2015.

3. Ablin RJ, Soanes WA, Gonder MJ: Immunologic studies of the prostate: A review. Int Surg 52:8-21, 1969.

4. Soanes WA, Ablin RJ, Gonder MJ: Remission of metastatic lesions following cryosurgery in prostatic cancer: Immunologic considerations. J Urol 104:154-159, 1970.