dinitrobenzenes and Skin-Neoplasms

This paper is a report of response rate (RR) and survival of 34 metastatic melanoma patients who received a dinitrophenyl (DNP)-modified autologous melanoma cell vaccine. In all, 27 patients started the vaccine as a primary treatment for metastatic melanoma and seven started it as an adjuvant, with no evidence of disease at the time, but had developed new metastases. Interleukin-2 (IL-2) was administered in 24 out of the 34 patients: 19 who progressed on vaccine alone and five who had the combination from start. Interleukin-2 was administered in the intravenous, bolus high-dose regimen (seven patients) or as subcutaneous (s.c.) low-dose treatment (17). Overall response for the entire group was 35% (12 patients out of 34), 12% having a complete response (CR) and 23% a partial response (PR). However, only two patients had tumour responses while on the vaccine alone, whereas the other 10 demonstrated objective tumour regression following the combination with IL-2 (two CR, eight PR), lasting for a median duration of 6 months (range 3-50 months). Of the 12 responding patients, 11 attained strong skin reactivity to the s.c. injection of irradiated, unmodified autologous melanoma cells. None of the patients with a negative reactivity experienced any tumour response. Patients with positive skin reactions survived longer (median survival - 54 months). The results suggest enhanced RRs to the combination of IL-2 and autologous melanoma vaccine. Skin reactivity to unmodified autologous melanoma cells may be a predictor of response and improved survival, and therefore a criterion for further pursuing of immunotherapeutic strategies.

Topics: Adjuvants, Immunologic; Adolescent; Adult; Aged; Antineoplastic Agents; Cancer Vaccines; Child; Combined Modality Therapy; Dinitrobenzenes; Disease Progression; Female; Humans; Interleukin-2; Male; Melanoma; Middle Aged; Neoplasm Metastasis; Skin Neoplasms; Survival Analysis; Treatment Outcome

We have previously reported a clinical trial of a human cancer vaccine consisting of autologous tumor cells modified with the hapten, dinitrophenyl (DNP), in patients with clinical stage III melanoma. Here we present a follow-up report expanded to 214 patients with 5-year follow-up.. Two hundred fourteen patients with clinical stage III melanoma (117 patients with stage IIIC and 97 patients with stage IIIB) who were melanoma-free after standard lymphadenectomy were treated with multiple intradermal injections of autologous, DNP-modified vaccine mixed with bacille Calmette-Guérin. Four vaccine dosage schedules were tested sequentially, all of which included low-dose cyclophosphamide. Patients were tested for delayed-type hypersensitivity (DTH) to autologous melanoma cells, both DNP-modified and unmodified, and to control materials.. The 5-year overall survival (OS) rate of the 214 patients was 44%. DTH responses to unmodified autologous melanoma were induced in 47% of patients. The OS of this DTH-positive group was double that of DTH-negative patients (59.3% v 29.3%; P <.001). In contrast, positive DTH responses to DNP-modified autologous melanoma cells and to purified protein derivative developed in almost all patients but did not affect OS. Surprisingly, the OS after relapse was also significantly longer in patients who developed positive DTH to unmodified tumor cells (25.2% v 12.3%; P <.001). Finally, the development of DTH was dependent on the schedule of administration of the vaccine, specifically, the timing of an induction dose administered at the beginning of the treatment program.. This study underscores the importance of the immunopharmacology of the autologous, DNP-modified vaccine and may be relevant to other cancer vaccine technologies.

Topics: Adjuvants, Immunologic; Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Cancer Vaccines; Combined Modality Therapy; Cyclophosphamide; Dinitrobenzenes; Female; Follow-Up Studies; Haptens; Humans; Hypersensitivity, Delayed; Male; Melanoma; Middle Aged; Mycobacterium bovis; Neoplasm Recurrence, Local; Skin Neoplasms; Survival Rate

Prostaglandins have been implicated in the immune suppression associated with the development of some tumours. Application of the prostaglandin synthetase inhibitor indomethacin, to murine skin prior to treatment with the chemical carcinogens benzo(a)pyrene (BP) or 7,12 dimethylbenz(a)anthracene (DMBA), restored contact sensitivity responses to 2,4-dinitrofluorobenzene in BP- but not DMBA-treated mice. However, indomethacin failed to restore antibody responses in either group of mice. Prolonged treatment with BP or DMBA led to cutaneous tumour formation. Indomethacin was found to delay the onset and reduce the size of tumours in BP- but not DMBA-treated mice. It is proposed that prostaglandin-induced suppression of cellular cutaneous immunity may play a role in BP- but not DMBA-induced cutaneous carcinogenesis.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antigen-Presenting Cells; Benzo(a)pyrene; Carcinoma, Squamous Cell; Dermatitis, Contact; Dinitrobenzenes; Immunity, Cellular; Indomethacin; Male; Mice; Mice, Inbred BALB C; Skin; Skin Neoplasms

Topics: Catechol Oxidase; Dinitrobenzenes; Humans; Melanoma; Monophenol Monooxygenase; Nitrobenzenes; Skin Neoplasms