Cryoimmunotherapy- an Update

by Richard J. Ablin, Ph.D.

Cryosurgery per se, as you may have undoubtedly read about elsewhere, aims at a local effect by the in situ cryogenic destruction of abnormal tissue, notably malignant, by the application of subzero temperatures. Concomitantly, its effect on a number of tissues, including the prostate, is the development of an immune response to proteins (antigens) of the tissue frozen. The immune response comprises one of the principal mechanisms of cryodestruction and has been reported to contribute to the eradication of the primary tumour and, in a number of cases, metastases. Nonetheless, many may initially view the immune response of less importance clinically than the physical cryogenic destruction of the tumour. However, the immune response may be decisive to attaining subsequent control of the tumour, most notably in the case of systemic disease.

For a more in depth discussion on the cryoimmune response and its application, i.e., cryoimmunotherapy, the interested reader is referred to a recent review on the subject by the author (In: Onik, G.M. et al., Eds. Percutaneous Prostate Cryoablation. Quality Medical Publ., Inc., St. Louis, 1995, p. 136).

Presentations on the subject of the immune response following cryosurgery at the recent 10th World Congress of Cryosurgery (Orlando, FL 29 October-1 November, 1998), suggested this brief update would be useful.

At the Session held at the Congress in Memory of Lloyd J. Ney, founder of Patient Advocates for Advanced Cancer Treatments (perhaps more familiarly known to many as PAACT), I was privileged to Moderate, two papers focused specifically on the prostate. The first paper, by myself, presented an overview of the concept and application of cryoimmunology and cryoimmunotherapy (outlined in brief in the foregoing) since the introduction of our initial and subsequent observations and those of others over the past 30 years.

The second presentation by Doctor Vladimir Mouraviev (St. Petersburg, Russia) reported 3-12 months interim results of an ongoing clinical trial of cryoimmunotherapy in patients with metastatic prostate cancer (Stage T4N1M1 [D2]). Patients were treated 2-days before cryosurgery of the prostate by subcutaneous injection of recombinant interleukin-1b (rIL-1b) followed by the intratumoural injection of rIL-1b at 1-day after cryosurgery. Pre- and postcryosurgical evaluation of select immunological parameters were suggestive of an immune response in association with the observed regression of what were described as lymph node and metastatic lesions in solid organs in 4 of 7 patients. These results are quite promising, but caution is urged in making any definitive conclusions in view of the limited number of patients and the short term follow-up.

A third scheduled, although not presented, report on the Program on the immune response following cryosurgery of the prostate was from the group of Doctor Gabriele Fontana (Savigliano, Italy). Doctor Fontana, together with Doctor Giovanni Sesia (Torino, Italy), was one of the pioneers of the use of cryosurgery for the treatment of prostate cancer in Europe. Doctor Fontana's group has demonstrated improvement on survival in prostate cancer patients treated with hormonal therapy plus cryosurgery vs. patients treated with hormonal therapy only. A small group of patients with advanced prostate cancer treated by cryosurgery and IL-2, showed what have been described as "good results". Doctor Fontana, in accord with the author of this report (RJA), emphasized enhancement and modulation of immune response to maximize the cryoimmune response.

While not specifically germane to prostate cancer, three other papers presented at theCongress are nonetheless important as they provided evidence of an immune response following the cryosurgical treatment of patients with other malignancies. These included the treatment of tracheal and bronchial tumours by Doctors M. Omar Maiwand (Middlesex, United Kingdom) and Milos Pesek (Plzen, Czech Republic). A third report, by Doctor Jan Zaloudik (Brno, Czech Republic) dealt with results of cryoimmunostimulation in combination with the local regional administration of cytokines in the treatment of liver metastases from colorectal cancer, malignant melanoma and sarcoma.

When considered with its capability to elicit an immune response, cryosurgery provides a "double-edged sword" to our therapeutic armamentarium and thereby, a way to treat localized and metastatic cancer. Unfortunately, in spite of the significant morbidity and complications associated with currently more accepted treatment modalities for prostate cancer (and other malignancies), the concept and application of cryoimmunotherapy remains as yet an unappreciated and under utilized form of therapy. Nonetheless, let us hope with the recent implementation of Medicare by the Health Care Financing Administration to provide reimbursement for cryosurgery for localized prostate cancer, we will see long overdue attention to utilization of cryosurgery, and with it, the generally favorable additional, if not needed, therapeutic benefit of the patient's immune response.

A reasonable question at this point is: Why in the consideration of the treatment of localized disease should one be concerned with the possible needed benefit of an immune response? The answer is that although patients may be judged clinically and radiographically to have organ confined disease, many, i.e., upwards of 50%, will have extracapsular extension, as well as the probability of occult micrometastatic disease at the time of diagnosis (Partin et al., J. Urol., 150:110, 1993). Therefore, a therapy, such as cryosurgery, which concomitantly provides local, as well as possibly systemic treatment, e.g., via the development of an immune response, is highly desireable. The validity of this earlier suggested approach for the treatment of prostate cancer by the author (RJA), may be seen from several currently ongoing trials combining other forms of local and systemic treatment, e.g., radiotherapy and androgen deprivation. The latter approaches, however, still carry with them their attendant side effects and lack the exquisite specificity of an immune response.

Many malignancies, including prostate cancer, are contrary to popular opinion, systemic diseases, which are not cured by currently thought of acceptable treatment modalities. Therefore, the use of a therapy, or the combination of therapies, i.e. combined-modality therapy, that provide localized and systemic treatment with minimal, if at all side effects, is critical. One such approach toward achieving this, as considered in this update, is cryosurgery.


Copyright 2000 Mark Haythorn