November 1998
V. Mouraviev, G.Prochorov, V.Konusova, A.Simbircev, A.Popovitch
Clinical Hospital of Russian Academy of Science, St.Petersburg, Russia

INTRODUCTION&OBJECTIVITIE: In an effort to enhance the T cells, several strategies have recently been explored aimed at creating therapeutic cancer vaccines. In case of tumor, as prostate cancer, for which the relevant tumor antigens are unknown, this approach has used the tumor cell itself as a source of antigen, modifying it in vitro to express immunomodulatory proteins such as cytokines. These studies have demonstrated in experiments that vaccination with tumor cells modified in this way frequently leads to the generation of systemic, tumor- specific immunity. In our opinion,the cryodestruction of prostate cancer may be as an optimal model of so-called "specific autovaccination".

METHODS: In an ongoing pilot study the standard palliative (single freezing) procedure of cryosurgical ablation of the prostate(CSAP) has been carried out in 5 patients with T4N1-3M1 (D2) stage and >6 months follow-up. Before it during 1-2 days we have injected subcutaneously the solution of recombinant human interleukin-1-b (rHuIL-1b) in dose 40 ng/kg (produced by Scientific Institution of High Pure Bioproducts, St.Petersburg, Russia). In next day after CSAP additionally we have performed the intratumor injection of this agent (up to 10 ng). For enhancing of immune response we have then continued this systemic immunotherapy during post-operative. Follow-up included the routine clinical investigation, prostatic specific antigen (PSA), X-rays and scintigraphy of scelet, computer tomography and magnetic nuclear resonance imaging of abdominal and pelvic cavity, thorough immunomonitoring.

RESULTS: In 3 cases we have investigated the clinical remission of metastatic lesions, biochemical significant failure of PSA (from 83 to 125 ng/ml initially to 15 - 45 consequently), improvement of quality of life, indirect features of increasing of tumor-specific immunity (increasing of quantitative parameters of antigen activation; enhancing of functional activity of lymphocytes, stimulation of IL-2, IL-8 etc.). It was a very important proposal to support this specific immune response not by means of consequential cryotherapy, but the repeated immunotherapy by rHuIL-1-b. In 1 case we have reached the partial immune response with regression of some metastases from solid organs (not osteolytic origin). In 1 case with terminal stage of D2 patient was died due to the polyorgan failure as the result of the toxic complications of the intensive scheme of cry-chemotherapy.

CONCLUSION: Our initial results of pilot-study encourage about possible efficacy of this therapeutic modality for advanced prostate cancer. In comparing with previous studies the enhancing of tumor-specific immunity may be achieved not at all by the consequential cryotherapy, but the repeated course of systemic immunotherapy by rHuIL-1-b. The continuation this study is needed to proven main idea futher.



- the cryogenic destruction of tumour and capacity to elicit an antitumour immune response forms the basis for the concept of cryoimmunotherapy (R.J.Ablin)
- since cytoreductive cryosurgery leaves dead tissue in situ to be resorbed over time, theoretically it can be likened to an vivo tumour vaccine in which tumour heterogeneous antigens, perhaps slightly changed or previously unexpected to the body's defense mechanisms, can be recognized
- cryoimmune response may additionally be tumouricidal to metastases
- developments in genetic engineering, permitting increased immunogenicity of tumours through transfection with expression vectors for various cytokines and redirected attention also to the concept of cryo-immuno-chemotherapy, provide further means by which to possibly enhance the local and systemic cryodestruction of tumours
- insufficient knowledge of precise role of cytoreductive surgery for advanced prostate cancer


- prostate carcinoma is largely a nonimmunogenic cancer
- damage of immune response mechanisms leads to tumour escape from immune surveillance
- native immunological response may be as a typical inflammation process
- concomitant destruction of immunocompetent cells
- antigen excess from multiple freezing at one setting may contribute to tumour growth and metastases progress

T R I A L 1

Phase I (7 pats)-

- r H IL-I beta: 5ng/kg i.v. b.i.d. on days 1-5 of weeks 1-2; and 10ng/kg s.c. on days 1-5 of weeks 8, 16; plus
- EMP 600mg/m2 i.v. b.i.d. on days 2-7 of weeks 1-3; and 300mg/m2 orally on days 1-7 of weeks 6-10, 12-16; plus
- Cytoreductive cryodestruction of prostate cancer by single-freezing cycle on days 3 of week 1
- Intralesional injection of rH IL-1b 10ng on day 3 ofweek 1 immediately after cryodestruction

T R I A L 2

Phase II (3 pats )- similar design as trial 1 plus
- r H IL-2: 0,25 MU/m2 i.v. b.i.d. on days1-5 of week 1; and 0,5 MU/m2 s.c. on days 1-5 of weeks 6,11; plus
- intralesional injection of r H IL-2 0,1 MU on days 3 of week 1 immediately after cryo (together with r H IL-1b)


1. Initial results of this combined modality- cryo-immuno-chemotherapy bring some hope to improve the efficacy of advanced stage therapy.
2. The cytoreductive cryodestruction may consider as a variant of so-called "autovaccination" of heterogeneous disseminated prostate cancer, particularly with capability to increase T-cells response by main cytokines and to reduce the toxicity of chemotherapy.
3. In vivo injection genetic engineering IL-1 and IL-2 combined with their systemic administration has been shown to eliminate/cease the clinical manifestation- bleeding, pain, obstruction, tumour growth and metastases progress.
4. The future prospects with possible goals of new researches are to elucidate the individual immune response of patients with advanced prostate cancer, identify tumour antigens, and isolate peptide antigens that will elicit a strong cellular immune response. Other researches may be aimed at defining the clinical parameters that can predict responses to cryo-immuno-chemotherapy.

Case report

58-years man, with terminal stage of D2 prostate cancer with pulmonary metastases and pneumonia was underwent by treatment under design of Trial 1 on 30th October 1997. After 1 month general status was stabilized, and the clinical remission of metastatic lesions of solid organs was noted as well as, biochemical significant failure of PSA (to 125 ng/ml initially to 45 consequently), improvement of quality of life, the obvious signs of increasing of T-cell immunity (cell contain providing activation markers- CD 25, HLA-II, CD 16; enhancing of functional activity of lymphocytes, production of IL-2, IL-8 etc.). It was a very important proposal to support this specific immune response by repeated immunotherapy regimens every 2- 3 months accordingly the rates of immune monitoring.
Follow-up -1 year: stable state, patient returned to occupational duty (professor- physics, chair of research department), good quality of life, normal voiding, PSA- 44 ng/ml.

Initial results of Phase I of Trial 1 (follow-up from 3months till 1 year)
Regression of lymph nodes & metastatic lesions of solid organs 4 pats
Stable status or non-progression of bone metastases 3 pats
Improvement of quality of life 4 pats
Elimination/ or ceasing of local symptoms 5 pats
Lethality- (with survival 0,5 and 11 months) 2 pats

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