Cellular Immunotherapy Study of Prostate Cancer Patients and Resulting IgG Responses to Peptide Epitopes Predicted From Prostate Tumor-associated Autoantigens

Abstract

The immunogenicity of a cellular immunotherapy using genetically modified vaccines to express α(1,3)galactosyl epitopes (αGal) was evaluated in advanced prostate cancer (PC) patients. In this dose escalation phase I study, we report safety, feasibility, and immunologic data of an immunotherapy composed of 2 human PC cell lines engineered to express αGal epitopes (HyperAcute-Prostate, HAP, NewLink Genetics). Eight patients received up to 12 biweekly vaccinations with HAP. Enrolled patients (aged range, 53-85 y) had American Joint Committee on Cancer stage IV, any T, any N, M1, Eastern Cooperative Oncology Group PS≤2, at least 1 prior hormonal treatment and <3 prior chemotherapies, adequate bone marrow and organ function, and albumin ≥3.0 g/dL. Serum IgG antibodies to synthetic peptides overexpressed in PC were determined by enzyme-linked immunosorbent assay. Results indicate that HAP immunotherapy induced humoral immune responses to autoantigens in 2 of 8 patients. These patients developed IgG antibody to multiple epitopes overexpressed in PC after immunization. These responding patients received higher doses of the immunotherapy suggesting a dose response. Two immunogenic proteins (prostate-specific membrane antigen, hepsin) belong to the extracellular molecules family participating in malignant cell invasion. Median overall survival for patients was 25.1 months with 1 patient surviving over 70 months with stable PSA and bone metastasis before expiring of other causes. Three of 8 patients showed PSA stabilization (>100 d). In conclusion, HAP immunotherapy induces IgG responses to epitopes from autoantigens overexpressed in PC suggesting dose-dependent effect. HAP represents a viable immunotherapy approach to induce immune responses against tumor cells and may provide clinical benefit with minimal toxicity.

Dendritic cells pulsed with prostate-specific membrane antigen in metastatic castration-resistant prostate cancer patients: a systematic review and meta-analysis

“…Characteristics of the six nonrandomized prospective cohort trials included for the review are summarized in the Table 1 . 25 , 27 , 28 , 29 , 30 , 31 Of these six studies, except for two studies having five and two groups of intervention, all other studies were single armed. Because of the aggregate nature of data, we could not identify patients positive for HLA-A0201 although the inclusion criteria among studies were similar enough to avoid significant bias.…”

“…Only two studies reported the OS of the sample population; Hemstreet et al reported OS of 25.1 months, and Tjoa et al (1999) reported OS of 4.8 months (which are not presented here). 25 , 31 However, these reports are significantly heterogenous in nature and most probably not reliable. The study by Tjoa et al (1999) had used GM-CSF in combination with DCs and was not included in the analysis.…”

“…However, the results from these studies cannot be compared because of very small sample size and weaker study design in the first study in contrast to the second. 9 , 31 There is a necessity to compare the survival benefits and antitumor efficacy of these DCs with the conventional chemotherapy regimen. Although a recent cohort study has shown 11 months longer median OS for patients receiving DCs pulsed with recombinant PSMA (rPSMA) and recombinant survivin (rSurvivin) peptides in contrast to the control group receiving docetaxel plus prednisone, the sample size of 11 patients per arm is too small to accept the results of this study as a generalizable answer.…”

Cancer Vaccines

“…The HyperAcute vaccines are made of tumour cell lines that have been genetically engineered to express the α(1,3)-galactosyltransferase enzyme in order to induce an hyperacute reaction with complement-and antibody-dependant cytotoxicity [135]. They have been tested in several malignancies including melanoma, pancreatic and prostate cancer [136][137][138] and showed encouraging results improving OS. This vaccine was further evaluated in two phase 3 clinical trials.…”

Optimizing the Immune System to Achieve Control of the Metastatic Malignant Lesion

“…Mounting evidence from both in-vitro and in-vivo studies at Precision Biologics and other research groups suggest that this process is represented mainly through a B cell response, producing the needed levels of the specific IgG1 that can bring tumor growth under control 2-5. Under normal circumstances however, the needed level of tumor antigen expression to induce the proper host response is low.…”