Cryoimmunotherapy, also referred to as cryoimmunology, is an oncological treatment for various cancers that combines cryoablation of tumor with immunotherapy treatment.[1] In-vivo cryoablation of a tumor, alone, can induce an immunostimulatory, systemic anti-tumor response, resulting in a cancer vaccine—the abscopal effect.[2] Thus, cryoablation of tumors is a way of achieving autologous, in-vivo tumor lysate vaccine and treat metastatic disease.[3][4] However, cryoablation alone may produce an insufficient immune response, depending on various factors, such as high freeze rate.[5] Combining cryotherapy with immunotherapy enhances the immunostimulating response and has synergistic effects for cancer treatment.[6]

Although, cryoblation and immunotherapy has been used successfully in oncological clinical practice for over 100 years,[7][8] and can treat metastatic disease with curative intent, it has been ignored in modern practice. Only recently has cryoimmunotherapy been resurrected to become the gold standard in cancer treatment of all stages of disease.[9]


Immunological effects resulting from the cryoablation of tumors was first observed in the 1960s.[10][11] Since the 1960s, Tanaka treated metastatic breast cancer patients with cryotherapy and reported cryoimmunological reaction resulting from cryotherapy.[12][13] In the 1970s, systemic immunological response from local cryoablation of prostate cancer was also clinically observed.[14][15][16] In the 1980s, Tanaka, of Japan, continued to advance the clinical practice of cryoimmunology with combination treatments including: cryochemotherapy and cryoimmunotherapy.[17] In 1997, Russian scientists confirmed the efficacy of cryoimmunotherapy in inhibiting metastases in advanced cancer.[18] In 2000s, China, following closely with the exciting developments, enthusiastically embraced cryoablation treatment for cancer and has been leading the practice ever since with cryoimmunotherapy treatments available for cancer patients in numerous hospitals and medical clinics throughout China.[19][20] In the 2010s, American researchers and medical professionals, started to explore cryoimmunotherapy for systemic treatment of cancer.[21]

Mechanisms of actionsEdit

Cryoablation of tumor induces necrosis of tumor cells. The immunotherapeutic effect of cryoablation of tumor is the result of the release of intracellular tumor antigens from within the necrotized tumor cells. The released tumor antigens help activate anti-tumor T cells, which destroy remaining malignant cells. Thus, cryoablation of tumor elicits a systemic anti-tumor immunologic response.[22][23][24]

The resulting immunostimulation from cryoablation may not be sufficient to induce sustained, systemic regression of metastases, and can be synergised with the combination of immunotherapy treatment and vaccine adjuvants.[25]

Various adjuvant immunotherapy and chemotherapy treatments can be combined with cryoablation to sustain systemic anti-tumor response with regression of metastases, including:

  • Injection of immunomodulating drugs (i.e.: therapeutic antibodies) and vaccine adjuvants (saponins) directly into the cryoablated, necrotized tumor lysate, immediately after cryoablation
  • Administration of autologous immune enhancement therapy, including: dendritic cell therapy, CIK cell therapy

See alsoEdit


  1. ^ Sidana Abhinav (2014). "Cancer immunotherapy using tumor cryoablation". Immunotherapy. 6 (1): 85–93. doi:10.2217/imt.13.151. PMID 24341887.
  2. ^ With improvements in breast imaging and image-guided interventions, there is interest in ablative techniques for breast cancer. Cryosurgery initiates inflammation and leaves tumor-specific antigens intact, which may induce an anti-tumor immune response.Tarkowski R, Rzaca M (2005). "Immunologic response to cryoablation of breast cancer". Gland Surg. 3 (2): 88–93. doi:10.3978/j.issn.2227-684X.2014.03.04. PMC 4115762. PMID 25083502.
  3. ^ Not only does it represent an alternative to surgical intervention, but it also creates a tumor-specific immune response stimulated by damaged cells. This cryoimmunologic response may contribute to controlling metastases far from the primary breast tumor. "Harnessing ultrasound-guided cryoablation for breast cancer". 2016. Cite journal requires |journal= (help)
  4. ^ We report the case of a patient with lung and bone metastases of RCC whose lung metastases disappeared after reconstruction using the resected specimen treated by liquid nitrogen for the bone metastasis. This 60-year-old female had a left RCC with multiple lung metastases and a left femoral bone metastasis at the time of diagnosis. After left nephrectomy followed by immunotherapy, we performed tumour excision and reconstruction with frozen recycled autograft. The lung metastases had disappeared by 10 months after surgery, while serum levels of interferon-gamma and interleukin-12 had increased. We postulate that the antitumour activity resulted from immunotherapy plus cryotreatment of her bone metastasis and believe that this case supports continued research into immunotherapy for cancer.Tsuchiya, Hiroyuki; Namiki, Mikio; Mizokami, Atsushi; Tanzawa, Yoshikazu; Takeuchi, Akihiko; Hayashi, Katsuhiro; Shirai, Toshiharu; Nishida, Hideji (2011). "Cryotreatment against Metastatic Renal Cell Bone Tumour Reduced Multiple Lung Metastases". Anticancer Research. 31 (9): 2927–2930. PMID 21868540.
  5. ^ Sabel MS, Su G, Griffith KA, Chang AE (2010). "Rate of freeze alters the immunologic response after cryoablation of breast cancer". Annals of Surgical Oncology. 17 (4): 1187–1193. doi:10.1245/s10434-009-0846-1. PMID 20033323. S2CID 30048369.
  6. ^ Haen, SP; Pereira, PL; Salih, HR; Rammensee, HG; Gouttefangeas, C (2011). "More Than Just Tumor Destruction: Immunomodulation by Thermal Ablation of Cancer". Clin Dev Immunol. 2011: 1–19. doi:10.1155/2011/160250. PMC 3254009. PMID 22242035.
  7. ^ History of Cryosurgery. 2008.
  8. ^ McCarthy EF (2006). "The Toxins of William B. Coley and the Treatment of Cancer". Iowa Orthop J. 26: 154–8. PMC 1888599. PMID 16789469.
  9. ^ "About Cryotherapy".
  10. ^ A relationship between thermal therapies and the immune system has been recognized since the 1960s, when an antibody response was seen following cryotherapy. The abscopal effect of cryotherapy has been reported as early as the 1970s [55, 56]. The concept of “cryoimmunology” originated in the 1960s when it was observed that serum anti-tumor antibodies develop after cryoablation [24, 57]. Anecdotal reports of the abscopal effect of cryotherapy in humans followed shortly thereafter in the 1970s. Mehta Amol (2016). "Thermal Ablative Therapies and Immune Checkpoint Modulation: Can Locoregional Approaches Effect a Systemic Response". Gastroenterol Res Pract. 2016: 1–11. doi:10.1155/2016/9251375. PMC 4802022. PMID 27051417.
  11. ^ Yantorno C, Soanes WA, Gonder MJ, Shulman S (1967). "Studies in cryo-immunology". Immunology. 12 (4): 395–410. PMC 1409203. PMID 4960713.
  12. ^ Tanaka (1982). "Immunological aspects of cryosurgery in general surgery". Cryobiology. 19 (3): 247–62. doi:10.1016/0011-2240(82)90151-1. PMID 7105777.
  13. ^ Richard J. Ablin (1998). "The Use of Cryosurgery for Breast Cancer". Arch Surg. 133 (1): 106. doi:10.1001/archsurg.133.1.106. PMID 9438770.
  14. ^ Soanes WA, Ablin RJ, Gonder MJ (1970). "Remission of metastatic lesions following cryosurgery in prostatic cancer: immunologic considerations". J Urol. 104 (1): 154–9. doi:10.1016/s0022-5347(17)61690-2. PMID 4987666.
  15. ^ Ablin, Richard J.; Fontana, Gabriele (1979). "Cryoimmunotherapy: Continuing Studies toward Determining a Rational Approach for Assessing the Candidacy of the Prostatic Cancer Patient for Cryoimmunotherapy and Postoperative Responsiveness". Eur Surg Res. 11 (4): 223–233. doi:10.1159/000128070. PMID 527611.
  16. ^ R. J. Ablin; et al. (1971). "Prospects for Cryo-Immunotherapy in Cases of Metastasizing Carcinoma of the Prostate". Cryobiology. 8 (3): 271–279. doi:10.1016/0011-2240(71)90050-2. PMID 5570410.
  17. ^ Tanaka (1985). "Cryotherapy" (in general surgery and related areas).". Gan No Rinsho. 31 (6 Suppl): 712–20. PMID 3897620.
  19. ^ Tumor treatment through cryotherapy was first invented by Americans in 1960s. Aimed at promoting the new technology, the ISC was founded in Austria in 1972. The technology matured with each passing day after over 30 years of development. In recent years, in particular, China, with its greater economic development and scientific and technological progress, has been playing a leading role in the world in terms of both theoretical research and clinical application of cryotherapy. As an efficient medical method for treating tumors, cryotherapy has been adopted by more and more medical institutions in China and has achieved remarkable cancer-treating effectiveness."China: New Chair of the International Society of Cryosurgery (ISC)". 2015. Archived from the original on 2016-10-20. Retrieved 2016-10-20.
  20. ^ Ross-Paul says that while to date there have been several dozen patients treated by cryoablation for breast tumors by Dr. Peter Littrup, a pioneer in the cryotherapy field, the Chinese, who began using cryoablation to treat breast cancer about the same time as Littrup, have treated more than 3,800 women using the method. “The fact that these tremendous advances in China have not been duplicated in the U.S. is disturbing,” Ross-Paul said."Minimally Invasive Breast Cancer Cryotherapy Largely Ignored in U.S., Says Advocate and 13-Year Survivor". 2016. Archived from the original on 2016-10-20. Retrieved 2016-10-20.
  21. ^ Veenstra JJ, Gibson HM, Freytag S, Littrup PJ, Wei WZ (2015). "In situ immunization via non-surgical ablation to prevent local and distant tumor recurrence". Oncoimmunology. 4 (3): e989762. doi:10.4161/2162402X.2014.989762. PMC 4404795. PMID 25949901.
  22. ^ Xu, Lisa X.; Liu, Ping; He, Kun; Zhang, Aili; Zhang, Yan; Zhu, Jun (2015). "Cryo-thermal therapy elicits potent anti-tumor immunity". Scientific Reports. 6: 27136. doi:10.1038/srep27136. PMC 4891716. PMID 27256519.
  23. ^ Cryosurgery initiates inflammation and leaves tumor-specific antigens intact, which may induce an anti-tumor immune response.Sabel (2005). "Immunologic response to cryoablation of breast cancer". Gland Surg. 3: 88–93. doi:10.3978/j.issn.2227-684X.2014.03.04. PMC 4115762. PMID 25083502.
  24. ^ Machlenkin, A.; Goldberger, O.; Tirosh, B.; Paz, A.; Volovitz, I.; Bar-Haim, E.; Lee, S. H.; Vadai, E.; Tzehoval, E.; Eisenbach, L. (2005). "Combined Dendritic Cell Cryotherapy of Tumor Induces Systemic Antimetastatic Immunity". Clinical Cancer Research. 11 (13): 4955–4961. doi:10.1158/1078-0432.CCR-04-2422. PMID 16000595.
  25. ^ Mehta Amol (2016). "Thermal Ablative Therapies and Immune Checkpoint Modulation: Can Locoregional Approaches Effect a Systemic Response". Gastroenterol Res Pract. 2016: 1–11. doi:10.1155/2016/9251375. PMC 4802022. PMID 27051417.

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