From: Proceedings 10th World Congress of Cryosurgery
Intraoperative cryosurgery and cytokine-potentiated cryoimmunostimulation

November 1998
J Zaloudik
Department of Surgical Oncology, Masaryk Memorial Cancer Institute, Brno, Czech Republic

Cryosurgery of tumors remains to be seen by many oncologists only as a local palliative procedure of marginal significance. Immunomodulatory potential of cryosurgery alone is considered to be weak, but few attention has been paid to its expansion with commercially available cytokines. Performing the superficial and intraoperative cryosurgery of tumors of various origin routinely since the beginning of the 1980's, I suggest to revive the concept of cryo immunostimulation on a novel basis. I summarize our findings as immunopathologically important features of the cryonecrosis:

1. Early hyperemia and hyperpermeability of capillaries allow an inflow of plasmatic protease inhibitors, which protect the tissue from initial autodigestion. This can be especially demonstrative considering the safety of pancreatic cryosurgery.

2. Epitopes of various tumor-associated antigens (TAAs) retain their binding specificity for some time after cryosurgery.

3. Leucocytic infiltration surrounding later the cryonecrosis is rich of mononuclear cells, which may be able to exert their functions on systemic level if they are properly stimulated and expanded.

4. Undesirable TH2 cellular and cytokine responses dominate in cancer patients primarily as well as after extensive cryosurgery or during systemic treatment with high-dose interleukin-2 (IL-2). Physiologically, however, the cytokines operate on local and/or regional level in a concerting action rather than as systemically activating soloists.

In light of Matzinger's "danger theory," the tumor tissue can be recognized more easily by the immune system when associated with cellular damage and signals of threat (heat shock proteins). Here I report on three concepts recently being under investigation, which may prove the utility of cryoimmunostimulation in combination with locoregional administration of cytokines.

Firstly, the cryosurgery of liver metastases from colorectal carcinoma has been successfully combined with intrahepatic chemo-immunotherapy; i.e., intra-arterial five fluorouracil and intra-portal interleukin-2 (Proleukin) or interferon-alpha (IFN-a). Secondly, cryosurgery of stage 11 and III malignant melanomas with repeated perilesional injections of interleukin-2, interferon-garnma (IFN-g) and granulocyte/monocyte colony stimulating factor (GM-CSF) is followed by subsequent radical operation two weeks later with an assumption of exerting the tumor-specific immune response against micrometastases. during the pre-operative immunostimulation phase. In this "in situcryovaccination concept, the GM-CSF serves as a stimulator of antigen-presentation by macrophages and other cells, INF-g as a promoter of the TH1 cellular response as an expander of lymphocytic response. It has been known since Rosenberg's observations that tumor-infiltrating lymphocytes expanded with IL-2 are hundred times more efficient in cytotoxicity than LAK cells from peripheral blood lymphocytes. Finally, the similar approach can be demonstrated in cryosurgery of residual soft tissue sarcomas after surgical debulking. But considering poor immunogenicity of these tumors, the long-term post-operative treatment with IFN-a as an inhibitor of neoangiogenesis should rather be investigated.

For several reasons there is unlikely, that these concepts could be validated by animal experiments. Being adapted to the current standard, but poorly effective therapeutic regimens in prognostically unfavorable or desperate oncological. situations, these concepts should be discussed and accepted for entering the clinical trials.

(Supported by a grant from the Czech Ministry of Health IGA MZ CR No. M/ 14-3)


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