dinitrobenzenes and Neoplasm-Metastasis

We have reported that treatment of melanoma patients with a vaccine consisting of autologous tumor cells modified with the hapten, dinitrophenyl (DNP), induced delayed-type hypersensitivity (DTH) to autologous, unmodified tumor cells. Moreover, this response was a significant and independent predictor of survival. We analyzed the vaccines prepared for 284 patients who were treated following resection of regional or distant metastases to determine whether the dose and composition correlated with immunological response. Regression analysis showed no significant association between the magnitude of this DTH response and the number of live (trypan blue-excluding) melanoma cells per dose. In fact, vaccines containing higher numbers or higher proportions of dead, but intact, tumor cells induced larger DTH responses to autologous unmodified tumor. The observation that dead tumor cells are immunogenic may be applicable to other cellular human cancer vaccines and underscores the need for applying pharmacological principles to cancer immunotherapy.

Topics: Cancer Vaccines; Cell Count; Cell Separation; Cell Survival; Dinitrobenzenes; Haptens; Humans; Hypersensitivity, Delayed; Injections, Intradermal; Melanoma; Neoplasm Metastasis; Survival Rate

We have devised a novel approach to active immunotherapy based on modification of autologous cancer cells with the hapten, dinitrophenyl (DNP). The treatment program consists of multiple intradermal injections of DNP-modified autologous tumor cells mixed with BCG. Administration of DNP-vaccine to patients with metastatic melanoma induces a unique reaction - the development of inflammation in metastatic masses. Histologically, this consists of infiltration of T lymphocytes, most of which are CD8+. These T cells usually produce gamma interferon in situ. Moreover, they represent expansion of T cell clones with novel T cell receptor structures. Occasionally, administration of DNP-vaccine results in partial or complete regression of measurable metastases. The most common site of regression has been small lung metastases. Administration of DNP-vaccine to patients in the post-surgical adjuvant setting produces a more striking clinical effect. We have treated 214 patients with clinically evident stage III melanoma who had undergone lymphadenectomy. With a median follow-up time of 4.4 years (1.8-10.4 years) the 5-year overall survival (OS) rate is 47% (one nodal site = 51%, two nodal sites = 33%). These results appear to be comparable to those obtained with high dose interferon. More recent studies suggest that this therapeutic approach is also applicable to ovarian cancer. There appear to be no insurmountable impediments to applying this approach to much larger numbers of patients or to developing it as a standard cancer treatment.

Topics: Antigens, Neoplasm; Autoantigens; Cancer Vaccines; Combined Modality Therapy; Dinitrobenzenes; Female; Haptens; Humans; Inflammation; Lymphocytes, Tumor-Infiltrating; Neoplasm Metastasis; Neoplasms; Ovarian Neoplasms

We have devised a novel approach to active immunotherapy based on modification of autologous cancer cells with the hapten, dinitrophenyl (DNP). The treatment program consists of multiple intradermal injections of DNP-modified autologous tumor cells mixed with BCG. Administration of DNP-vaccine to patients with metastatic melanoma induces a unique reaction- the development of inflammation in metastatic masses. Histologically, this consists of infiltration of T lymphocytes, most of which are CD8+. These T cells usually produce interferon-gamma in situ. Moreover, they represent expansion of T-cell clones with novel T-cell receptor (TCR) structures. Occasionally, administration of DNP-vaccine results in regression of measurable metastases. The most common site of regression has been small lung metastases. Administration of DNP-vaccine to patients in the postsurgical adjuvant setting produces a more striking clinical effect. Of 62 patients with clinically evident stage III melanoma who had undergone lymphadenectomy, the 5-year relapse-free survival rate was 45% and the overall survival rate was 58%. These results appear to be better than those obtained with high-dose interferon, although a randomized phase III trial is required to prove that point. A recent phase I study suggests that this therapeutic approach is also applicable to stage III ovarian cancer. There appear to be no insurmountable impediments to applying this approach to much larger numbers of patients or to developing it as a standard cancer treatment.

Topics: Animals; Cancer Vaccines; Clinical Trials as Topic; Dinitrobenzenes; Female; Haptens; Humans; Hypersensitivity, Delayed; Immunotherapy, Active; Inflammation; Lung Neoplasms; Male; Melanoma; Mycobacterium bovis; Neoplasm Metastasis; Ovarian Neoplasms; T-Lymphocytes; Tumor Cells, Cultured

Topics: 9,10-Dimethyl-1,2-benzanthracene; Acrylates; Adenocarcinoma; Alkylating Agents; Animals; Antibody Formation; Antigens, Neoplasm; Benzyl Compounds; Breast Neoplasms; Dinitrobenzenes; Female; Humans; Methacrylates; Mice; Mice, Inbred C3H; Neoplasm Metastasis; Neoplasm Transplantation; Neoplasms, Experimental; Transplantation, Homologous

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

Topics: Cyclophosphamide; Cytotoxicity, Immunologic; Dinitrobenzenes; Haptens; Humans; Immunotherapy, Active; Melanoma; Neoplasm Metastasis; Survival Analysis; T-Lymphocytes

We used mice from which the primary 410.4 mammary carcinoma had been surgically excised to assess the anti-metastatic activity of low-dose cyclophosphamide (CY) followed by vaccination with dinitrophenyl (DNP)-modified, irradiated, autologous tumor cells (ATC) admixed with bacille Calmette-Guérin (BCG). Our studies revealed that CY treatment of mice followed by vaccination with DNP-modified. irradiated, ATC admixed with BCG improved the relapse-free survival compared to the survival of mice receiving either CY followed by vaccination with unmodified, irradiated, ATC admixed with BCG, or saline (control group). In addition, our studies demonstrated the importance of CY administration in eliciting the therapeutic effect of DNP-modified ATC vaccine against metastatic disease. The therapeutic effect of CY followed by DNP-modified ATC vaccine was abrogated by depletion of CD4(+) or CD8(+) T-cells, illustrating the importance of both T-cell subsets for the anti-metastatic effect of this therapeutic protocol. In addition, neutralizing anti-IFN-gamma monoclonal antibody (mAb), or neutralizing anti-tumor necrosis factor (TNF) mAb reduced the relapse-free survival of mice treated with CY followed by DNP-modified ATC vaccine, indicating the importance of both cytokines for the realization of the anti-metastatic effect of this therapeutic protocol. Since the therapeutic protocol used in our studies was similar to that employed by Berd et al. as postsurgical adjuvant therapy in cancer patients and yielded a comparable anti-metastatic effect, the information obtained from the current studies with our clinically relevant experimental tumor model is expected to shed light on the mechanism(s) by which the anti-metastatic effect of this post-surgical adjuvant therapy is realized in cancer patients.

Topics: Animals; Cancer Vaccines; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cyclophosphamide; Dinitrobenzenes; Female; Haptens; Interferon-gamma; Mice; Mice, Inbred BALB C; Neoplasm Metastasis; Neoplasms, Experimental; Tumor Necrosis Factor-alpha