Delayed Disease Progression after Allogeneic Cell Vaccination in Hormone-Resistant Prostate Cancer and Correlation with Immunologic Variables

Abstract

Purpose: There are a significant number of patients with asymptomatic hormone-resistant prostate cancer who have increasing prostate-specific antigen (PSA) levels but little or no evaluable disease. The immunogenicity and minimal toxicity associated with cell-based vaccine therapy makes this approach attractive for these patients. Experimental Design:We have evaluated a vaccine comprising monthly intradermal injection of three irradiated allogeneic prostate cell lines (8 Â 10 6 cells each) over 1year. The first two doses were supplemented with bacille Calmette-Gue¤ rin as vaccine adjuvant. Twenty-eight hormoneresistant prostate cancer patients were enrolled. Patients were assessed clinically and PSA levels were measured monthly. Radiologic scans (X-ray, computed tomography, and bone scan) were taken at baseline and at intervals throughout the treatment period. Comprehensive monthly immunologic monitoring was undertaken including proliferation studies, activation markers, cytokine protein expression, and gene copy number. This longitudinal data was analyzed through predictive modeling using artificial neural network feed-forward/back-propagation algorithms with multilayer perceptron architecture. Results: Eleven of the 26 patients showed statistically significant, prolonged decreases in their PSA velocity (PSAV). None experienced any significant toxicity. Median time to disease progression was 58 weeks, compared with recent studies of other agents and historical control values of around 28 weeks. PSAV-responding patients showed a titratable T H 1 cytokine release profile in response to restimulation with a vaccine lysate, while nonresponders showed a mixed T H 1 and T H 2 response. Furthermore, immunologic profile correlated with PSAV response by artificial neural network analysis. We found predictive power not only in expression of cytokines after maximal stimulation with phorbol 12-myristate 13-acetate, but also the method of analysis (qPCR measurement of IFN-g > qPCR measurement tumor necrosis factor-a > protein expression of IFN-g

Allogeneic gene-modified tumor cells (RCC-26/IL-7/CD80) as a vaccine in patients with metastatic renal cell cancer: a clinical phase-I study

“…Mocellin et al 1 published a comprehensive review of these studies in 2004 (webtables I and II), additional clinical studies have been recently published. 2,[25][26][27][28][29] In RCC, autologous tumor cells were retrovirally modified to secrete granulocyte-macrophage colony stimulating factor. Use of granulocyte-macrophage colony stimulating factor-secreting autologous tumor cells was feasible and safe; after vaccination of RCC patients with advanced disease strong DTH reactions of the skin were observed, together with cellular infiltrates at the injection site as well as occasional immunological and clinical responses.…”

Immunology and immunotherapy approaches for prostate cancer

“…180 A different allogeneic whole-cell vaccine composed of irradiated prostate cell lines OnyCap23, LNCaP and P4E6 demonstrated a decreased PSA velocity in 11 of 26 patients with HRPC and a longer median TTP (58 weeks), compared with other studies (28 weeks). 185 Another approach using a xenogeneic tissue vaccine has recently been shown to stimulate protective immunity against human PC cells. 186 …”

Biomarkers for the Development of Cancer Vaccines

“…Given that the proposed mechanism of action requires that the vaccine will be broken down into its constituent peptides, it follows that the HLA type of the vaccine is of secondary importance, since antigen processing will occur regardless of the patient's tissue-type. Indeed, it could be argued that an HLA mismatch might actually be a more potent vaccine because the host versus graft response, initiated by the presence of 'wrong' HLA molecules, may amplify the reaction [28]. Unfortunately, the encouraging Phase II trials with Canvaxin™ in melanoma [29] have not been followed by positive…”

“…Multilayer perceptron (MLP) artificial neural networks (ANNs) (Figure 1) have been used to develop predictive numerical models that may discriminate between responders and nonresponders to vaccination based on a range of immunological markers [28]. This approach has led to the development of diagnostic models that have good predictive performance with high specificity and sensitivity for blind data.…”

“…Therefore, immune monitoring of these trials is particularly challenging and must, by definition, include multiple parameters. In a recent Phase IIa trial [28], Onyvax produced a database of 20,000 data points, encompassing some 36 variables (Table 2). The correlation of these multiple parameters is complex and cannot be simplified into a two-dimensional model.…”