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The use of cryosurgery to ablate tumors is expanding, primarily due to its technical ease and minimal morbidity. A potential secondary advantage to the in situ freezing of malignant disease is the cryo-immunologic response, the generation of an anti-tumor immune response triggered by the natural absorption of the malignant tissue. While initially proposed based on clinical observations of distant disease regressing after cryoablation of a primary tumor, results from preclinical studies have been mixed and the existence of a cryo-immunologic response has been controversial. Recent studies have shed light on the potential mechanism by which cryoablation may modulate the immune system, also reveals that both immunostimulatory and immunosuppressive responses may be triggered. This article reviews the existing evidence regarding tumor cryo-immunology and puts forward hypotheses regarding patient, tumor and technical factors that may influence the resultant immune response and warrant further investigation.

Cryoablation of cancer leaves tumor-associated antigens intact in an inflammatory microenvironment that can stimulate a regional anti-tumor immune response. We examined whether cryoablated tumor draining lymph nodes (CTDLN) as adoptive immunotherapy may be an effective immunotherapeutic approach in the adjuvant treatment of breast cancer. BALB/c mice with MT-901 mammary adenocarcinoma tumors underwent cryoablation, resection or no treatment and tumor draining lymph nodes were harvested. Cryoablation resulted in only a mild increase in the absolute number of T-cells but a significant increase in the fraction of tumor-specific T-cells as evidenced on IFN-gamma release assay. FACS analysis demonstrated no significant relative shift in the proportion of CD4(+) or CD8(+) cells. The adoptive transfer of CTDLN resulted in a significant reduction of pulmonary metastases as compared to TDLN from either tumor-bearing mice or mice who underwent surgical excision. Cryoablation prior to surgical resection of breast cancer can be used as a method to generate effector T-cells for adjuvant adoptive cellular immunotherapy.

Given the ease of delivery and patient comfort associated with cryoablation, and its success in other areas, there has been significant interest in cryoablation for gynecologic care. In some cases, cryoablation has proved a viable alternative, while in other areas, there are still challenges to be met. For two of the most common gynecologic disorders; fibroid tumors and excessive uterine bleeding, the use of cryoablation has been examined. In both cases, cryoablation is one of several established and experimental therapeutic options, with relative advantages and disadvantages compared with alternatives. Cryoablation has also been used in the treatment of gynecologic malignancies. For some cancers, while primary ablation has been studied, the use of cryoablation has been primarily palliative, in cases where surgical removal was not appropriate. In other cases, such as cervical cancer, cryotherapy may play a role in the management of early stage disease (cervical intraepithelial neoplasia). This presentation will examine the role of cryoablation in women’s health, including its limitations and indications compared with alternative therapies.

The surgical management of breast cancer has seen a radical evolution over the past several decades, characterized by equal or improved outcomes with significantly less morbidity. Eradication of the primary tumor has progressed from radical mastectomy (and extended radical mastectomy), through modified radical mastectomy, to lumpectomy. These changes have been facilitated by a multitude of factors, including improvements in technology and screening, better-quality and more widely used adjuvant therapies, and countless patients participating in multi-institutional prospective, randomized trials. The next, seemingly inevitable, step in the evolution of breast cancer therapy would be the replacement of lumpectomy, at least for a select group of patients, with non-surgical methods for destroying the tumor. Cryoablation has emerged as an alternative to surgery for tumors of the skin, prostate, kidney, liver and bone, and given recent advances in breast imaging, and our ability to target non-palpable lesions, it seems logical that breast cancer would be an ideal clinical target. However, adoption of cryoablation for breast cancer has proven challenging, with several obstacles still to overcome. This presentation will review the clinical experience to date with breast cancer cryoablation and some of the hurdles to its clinical implementation.

Much of the interest in cryoablation for malignant disease was prompted by observations that after freezing a primary lesion, distant, un-treated sites of disease show regression. This was presumed to be secondary to the generation of an anti-tumor immune response, stimulated by the ablation and resorption of the tumor, a concept known as “cryo-immunology”. As our knowledge of the components of the immune system and their interactions in the generation, or suppression, of an immune response has increased, we have greater understanding of how freezing a tumor in situ might stimulate an anti-tumor response. However, while both pre-clinical and clinical research suggests a pro-inflammatory response to cryoablation, this may not be potent enough to influence clinical outcomes. Our improved understanding of the immunologic response may allow us to both direct and augment the anti-tumor response stimulated by tumor cryoablation. New immunotherapies, such as anti-CTLA4 or anti-PD1 may serve as ideal adjuvants to cryoablation in order to generate clinically significant immune responses.

With improvements in technology, cryoablation as an alternative to surgery, has been used to treat cancers of the skin, prostate, liver, lung and bone. There is significant interest in cryoablation of breast cancer. Potential advantages over lumpectomy include the minimally invasive nature of the treatment, improved cosmetic results, patient comfort, decreased costs and the possible immune response to the ablated tissue. Several pre-clinical and clinical studies have demonstrated both the feasibility of breast cancer cryoablation and the generation of an anti-tumor immune response, and clinical experience with cryoablation of benign breast tumors is growing. The on-going American College of Surgeons Oncology Group Trial Z1072, a phase II trial examining the success of breast cancer cryoablation, is an important first step in possibly replacing lumpectomy with cryoablation for a subset of breast cancer patients. This discussion will review the breast cryoablation literature to date and discusses the directions the field needs to move into realize that goal.

Cryoablation as a cancer therapy dates back over one hundred years, however recent advances in technology have greatly expanded its clinical potential. Much of the interest in cryoablation centers around early observations that after freezing a primary lesion, distant, un-treated sites of disease began to regress. It was believed that this was secondary to cryoablation stimulating an anti-tumor immune response. This prompted multiple pre-clinical studies examining the impact of cryoablation on the immune response and the mechanisms involved. While most of these studies validated the ability of cryoablation to stimulate a tumor recognition by the immune system, some studies demonstrated the opposite; tumor bearing animals treated by cryoablation had diminished responses and increased tumor growth compared to controls. As our knowledge of the components of the immune system and their interactions in the generation, or suppression, of an immune response has increased, as well as our understanding of the mechanisms by which freezing leads to cell death, the immunomodulation seen with cryoablation is becoming clearer. Many questions still remain, but given the tremendous clinical potential in having a local therapy that could also have systemic benefits, further research in this area is strongly warranted. This talk will review the history of cryosurgery for the treatment of cancer; detail the mechanisms by which cryoablation leads to cancer cell death, and how this can be altered by variations in cryosurgical technique; and describe the pre-clinical data examining the relationship between cryoablation-induced cell death and both stimulatory and suppressive immune responses.