Metastatic melanoma patients who were treated with patient-specific vaccines consisting of dendritic cells loaded with autologous tumor cells had a 5-year survival of over 50%. Enzyme-linked immunospot (ELISPOT) has been used to detect antigen reactive T cells as a means of determining immune response. We wished to determine whether IFN-gamma secretion in an ELISPOT assay was prognostic or predictive for survival following treatment. Peripheral blood mononuclear cells (PBMCs) collected at weeks 0 and 4 were evaluated by ELISPOT assay for response to autologous tumor cells. Overall, there was slight increase in the number of tumor reactive lymphocytes from week 0 to week 4. Using >5 spots/100 K PBMC as the cutoff, a log-rank analysis revealed only a slight statistical significance in overall survival for patients who lacked tumor reactive PBMCs at week 4. The sensitivity of ELISPOT in the context of patient-specific cellular vaccines is unclear.

The use of whole cell tumor vaccines and various means of loading antigen onto dendritic cells have been under investigation for over a decade. Induction of apoptosis and the exposure of immune-stimulating proteins are thought to be beneficial for the use in immunotherapy protocols, but conclusive evidence in the clinical setting has been lacking. Incubation of melanoma cell lines with interferon-gamma (IFN-γ) increased phosphatidylserine and calreticulin exposure, but not in the IFN-γ-resistant cell line Lu-1205. Short-term autologous melanoma cell lines used for loading dendritic cells for immunotherapy showed differential response to the pro-apoptotic effects of IFN-γ. These IFN-γ-treated tumor cells (TCs) were irradiated and used for loading antigen for dendritic cell therapy. A log-rank comparison of survival for patients whose TCs were found to be either sensitive (upregulated phosphatidylserine and calreticulin) or insensitive to IFN-γ revealed a strongly significant correlation to progression-free (p = 0.003) and overall survival (p = 0.002) favorably in those patients whose cell lines were resistant to the proapoptotic effect of IFN-γ. These results suggest that the use of IFN-γ in anti-melanoma dendritic cell-based immunotherapy may only be beneficial when the cells do not undergo apoptosis in response to IFN-γ and support the contention that the use of some apoptotic cells in vaccines may be detrimental.

8555 Background: Patient-specific vaccines utilizing proliferating tumor cells, or tumor stem cells, may be the ideal products for active specific immunotherapy. Methods: Eligible patients had recurrent or metastatic melanoma from which a cell line was established, expanded to 200 million cells, incubated with interferon-gamma, irradiated and cryopreserved. Autologous dendritic cells (DC) were derived from peripheral blood mononuclear cells cultured in IL-4 and GM-CSF. DC were incubated with the irradiated tumor cells, then cryopreserved in 20- million-cell aliquots, which were thawed, washed and suspended in 500 micrograms of GM-CSF for injection. Treatment consisted of s.c. injections weekly × 3, then monthly × 5 in a 2-stage phase II trial with two stratifications. Patients were characterized as having objectively measurable disease (OMD) or non-measurable disease (NMD). Plans were to enroll 30 to 80 patients: 15 to 40 with OMD, 15 to 40 with MD. Objectives were to determine safety, frequency of conversion of delayed type hypersensitivity (DTH) reactions to irradiated autologous tumor cells, objective response rate (ORR) using RECIST criteria, progression-free survival (PFS), overall survival (OS), and comparison to a historical control group. Results: Between January 2001 and April 2006, 55 patients were enrolled; 53 were eligible and evaluable. The 30 men and 23 women had a median age of 50 years; 15 had OMD and 38 NMD. Patients received an average of 7.4 vaccinations out of a possible 8. Treatment was well- tolerated. 25% had a positive tumor DTH test: 1 at baseline, 7 after 3 injections, 5 after 8 injections. ORR was 0/15. Follow up for the 39 surviving patients ranges from 7 to 67 months with a median of 30 months. Median PFS is 7.1 months with 24 patients remaining progression-free. Only 14 patients have died; median OS has not been reached. 5-year projected survival is 70%; 20 patients are alive 2.5 to 5.5 years from start of vaccine. OS is better than observed for 48 comparable patients that we treated previously in a trial with irradiated tumor cells without DC (p=0.016). Conclusion: This patient-specific vaccine approach is feasible, safe, associated with encouraging survival, and warrants further investigation. No significant financial relationships to disclose.

7018 Background: Lucanix (L) is a non-viral gene based allogeneic tumor cell vaccine which demonstrates enhancement of tumor antigen recognition as a result of Transforming Growth Factor (TGF-β2) inhibition. Methods: We performed a randomized dose variable phase II trial involving stage IIIB/IV non small cell lung cancer (NSCLC). Each patient received one of 3 doses (1.25, 2.5, 5.0x107 cells/injection) of L, given intradermally, to a maximum of 16 injections either monthly or every other month. Immune function, safety and anticancer activity were monitored. Results: Sixty-one patients (15 IIIB/ 46 IV; 51/61 (84%) ≥ prior cytotoxic therapy), received a total of 417 vaccinations. No significant (≥ grade 3) adverse events probably or definitely associated with administration of the vaccine were observed. A dose-related survival difference was demonstrated in patients who received ≥ 2.5 × 107 cells/injection versus those who received <2.5 × 107 cells/injection (p=0.0151). The percent of patients surviving 1 and 2 years was 61% and 52% for the high dose group and 40% and 13% for the low dose group. Fifteen percent of patients achieved a partial response. Cytokine production (IFN-γ, p=0.006; IL-6, p=0.004; IL4, p=0.007) was induced, antibody mediated response to vaccine HLA antigen was observed (p=0.014) and cell mediated response showed a correlation trend (p=0.086) in patients achieving stable disease or partial response (15%) compared to those with progressive disease. Conclusions: In conclusion, L is safe and well tolerated. A survival advantage is suggested in patients who receive ≥ 2.5x107 cells/injection thereby supporting the justification for further phase III evaluation. Phase III investigation is recommended. [Table: see text]

This paper presents a reanalysis of a randomized clinical trial conducted by the Cancer and Leukemia Group B (CALGB, Bethesda, MD, USA). This trial found a significant benefit of combination chemotherapy followed by irradiation (CTRT) in comparison to radiotherapy alone (RT) for the treatment of nonsmall cell lung cancer. The validity of the results obtained and the decision to terminate taken by the CALGB, were assessed using sequential methods. The reliability and efficiency of sequential methods were also assessed for this study. Two sequential designs were used: the triangular and the restricted procedure. Initial analyses were conducted with the data from patients actually recruited, adjusting for important prognostic variables at any interim analysis. As a confirmatory technique, a continuation of the trial was simulated, sampling extra patients under the assumption of no treatment difference, preserving the effect of the prognostic variables. Using the results from the 155 patients recruited by the CALGB (88 deaths at termination and 136 after follow-up), the sample path stayed within the continuation region of both sequential designs considered. An underpowered sequential analysis showed significant superiority of CTRT over RT (95% confidence interval (95% CI) 0.50-0.96, p=0.03 for the triangular; 95% CI 0.37-0.88, p=0.01 for the restricted procedure). Conventional analysis of the follow-up data also showed significant superiority of CTRT. The trial extended with simulated data ended at 60 months with 251 patients (178 deaths), showing significant superiority of CTRT under both designs (95% CI for hazard ratio 0.55-0.97). The two sequential procedures would have led to the same conclusion as that reached by the Cancer and Leukemia Group B, still achieving considerable savings in patients recruited and time over the conventional design. The data simulated under the rather conservative null hypothesis did not reverse the positive result claimed by the Cancer and Leukemia Group B.

Malone, C; Mackintosh, A D; Schiltz, P M*; Beutel, L; Spencer, K; McGee, JMC; Dillman, R O* Author Information

Dillman, R. O.; Soori, G.; Tai, D. F.; Honeycutt, P.; DePriest, C.; Church, C. Author Information

Dillman, R. O.; Soori, G.; Tai, D. F.; Bury, F. M.; DePriest, C.; Church, C. Author Information

Malone, C.; Schiltz, P. M.; Nayak, S. K.; Macintosh, R.; Shea, M.; Dillman, R. O. Author Information

Dillman, R. O.; Nayak, S. K.; O'Connor, A. A.; Schiltz, P. M.; Austin, K.; Hendricks, C. Author Information

Schiltz, P. M.*; Nayak, S. K.*; Yang, X-F.a; Wormsley, S. B.a; Dillman, R. O.* Author Information

Eight patient case vignettes are presented to illustrate the possible relationship between melanoma and pregnancy. We pose 10 questions regarding the risk and prognosis and answer them based on information in the medical literature. Key conclusions are that there is no evidence that the risk for melanoma is influenced by pregnancy; there is no evidence that abortion in pregnant women diagnosed with melanoma is therapeutic for the mother or necessary to prevent melanoma in the fetus; although as a group, pregnant women diagnosed with melanoma may have a somewhat worse prognosis compared with nonpregnant controls, this difference disappears when patients are matched for factors including age, location and depth of primary, or stage of disease; and there is still a concern that pregnant women may present with more invasive or advanced disease due to hormonal or growth factor effects or delays in diagnosis because changes are attributed to pregnancy.

Hoag Cancer Center, Newport Beach, California, Williamson Medical Center and NBSG, Franklin, Tennessee

Cancer BiotherapyVol. 10, No. 3 Whither Magic Bullets and Guided Missiles: Monoclonal Antibodies 20 Years LaterRobert O. DillmanRobert O. DillmanSearch for more papers by this authorPublished Online:17 Jul 2009https://doi.org/10.1089/cbr.1995.10.177AboutSectionsPDF/EPUB ToolsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail FiguresReferencesRelatedDetailsCited ByMonoclonal antibody therapyMonoclonal antibody therapyMonoclonal Antibody Therapy for Lymphoma. An UpdateCancer Practice, Vol. 9, No. 2Monoclonal Antibodies in the Treatment of Malignancy: Basic Concepts and Recent Developments30 November 2001 | Cancer Investigation, Vol. 19, No. 8Best hope or last hope: access to phase III clinical trials of HER-2/neu for advanced stage breast cancer patientsJournal of Advanced Nursing, Vol. 31, No. 2Magic Bullets at Last! Finally—Approval of a Monoclonal Antibody for the Treatment of Cancer!!! Robert O. Dillman29 January 2009 | Cancer Biotherapy & Radiopharmaceuticals, Vol. 12, No. 4 Volume 10Issue 3Jan 1995 To cite this article:Robert O. Dillman.Whither Magic Bullets and Guided Missiles: Monoclonal Antibodies 20 Years Later.Cancer Biotherapy.Jan 1995.177-180.http://doi.org/10.1089/cbr.1995.10.177Published in Volume: 10 Issue 3: July 17, 2009PDF download

Journal of Immunotherapy with Emphasis on Tumor Immunology: August 1995 - Volume 18 - Issue 2 - p 128