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Programmed Death 1 Receptor (PD-1)-mediated Immunomodulatory Effects in Pancreatic Cancer
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Ashu Shah, Catherine Orzechowski, Maneesh Jain
Induction of endogenous anti-tumor T cell response by the use of therapeutic vaccines and/or neoadjuvant treatment has resulted in specific treatment with minimal toxicity in PDAC patients and genetically engineered mouse model of pancreatic cancer [56, 78]. GVAX (granulocyte-macrophage colony-stimulating factor (GM-CSF) secreting, allogeneic PDAC vaccine), a vaccine-based immunotherapy, when administered to PDAC patients demonstrated for the first time that immune therapies can convert immune quiescent tumors to immunogenic tumors, amenable to checkpoint blockade therapies [11, 79]. This was the first study to show that vaccination induced the formation of intratumoral lymphoid aggregates and gene signature analysis of the isolated aggregates was indicative of diminished Tregs activity, augmented Th17 pathway, and upregulation of PD-1 and PD-L1 axis. In another preclinical study, GVAX treatment showed upregulation of PD-L1 on pancreatic tumor cells and treatment with anti-PD-1 antibodies resulted in IFNγ secretion from infiltrated effector T cells [80] which is in line with observations made by Lutz et al. in human subjects. An alternative approach for developing neo-antigen based vaccine, based on neoepitopes, accumulated as a result of genetic mutations, for PDAC could also lead to optimal anti-tumor response by combination with immune checkpoint blockade molecules [67, 81].
Lung Cancer Vaccines
Published in Kishan J. Pandya, Julie R. Brahmer, Manuel Hidalgo, Lung Cancer, 2016
Cheryl Ho, Oliver Gautschi, Primo N. Lara, David R. Gandara, Angela M. Davies
In an effort to potentiate the effect of the vaccine, low-dose immunomodulatory cyclophosphamide has been added to GVAX therapy. A randomized phase II trial was conducted using GVAX, (CG8123) with or without cyclophosphamide (74). Although there was a trend to of improved outcomes with the addition of cyclophosphamide, it was not statistically significant and there was no improvement in progression-free survival (3.8 months without vs. 5 months with cyclophosphamide), or overall survival (5.4 months vs. 9.6 months).
Investigational luteinizing hormone releasing hormone (LHRH) agonists and other hormonal agents in early stage clinical trials for prostate cancer
Published in Expert Opinion on Investigational Drugs, 2019
Nirmish Singla, Rashed A. Ghandour, Ganesh V. Raj
There are several other non-hormonal agents currently under investigation for the treatment of prostate cancer, often studied in combination with hormonal agents. Examples include experimental immunotherapies, PI3K inhibitors, tyrosine kinase inhibitors, proteasome inhibitors, and Bcl-2 inhibitors, among others. Experimental immunotherapies have generated significant interest including therapeutic vaccines, oncolytic virus therapies, checkpoint inhibitors, adoptive cell therapies, adjuvant immunotherapies, cytokines, and monoclonal antibodies. For example, the results of a phase I/II randomized trial of neoadjuvant degarelix with or without the combination allogeneic cellular vaccine cyclophosphamide/GVAX in high-risk prostate cancer prior to radical prostatectomy (NCT01696877) were recently presented [76]. The immunogenicity of GVAX is felt to be enhanced by androgen ablation and low-dose cyclophosphamide.
Autophagosome-based strategy to monitor apparent tumor-specific CD8 T cells in patients with prostate cancer
Published in OncoImmunology, 2018
Rieneke van de Ven, Traci L. Hilton, Hong-Ming Hu, Christopher J. Dubay, Daniel Haley, Christopher Paustian, Sachin Puri, Walter J. Urba, Brendan D. Curti, Sandra Aung, Bernard A. Fox
To test whether UbiLT3 DRibbles could be used to monitor the generation of a cancer-vaccine induced immune response, we isolated PBMC from patients with metastatic CRPC, who were vaccinated with prostate GVAX. From the 17 patients included in this trial, post GVAX PBMC samples (week 12) were available from 12/17 patients. No objective clinical responses were observed in any of the patients treated on this trial. These patients were very sick and did not receive any checkpoint blockade in addition to the prostate GVAX vaccine to overcome tumor-induced immune suppression.28,29 Two patients in cohort C and one patient in cohort B displayed an increase in prostate-specific antigen doubling time (PSA-DT) post-treatment, suggestive of reduced tumor growth. Additional clinical assessment and immune monitoring performed for this trial will be described elsewhere (Curti et al., and Puri et al. manuscripts in preparation).
Recent advances in the management of pancreatic adenocarcinoma
Published in Expert Review of Anticancer Therapy, 2018
Yusuf Karakas, Sahin Lacin, Suayib Yalcin
A therapeutic vaccine aims to stimulate an immune reaction against tumor-specific or tumor-related antigens, targeting the immune system to destroy malignant cells expressing these antigens. Numerous studies of vaccines, either alone or with other therapies, have been performed. The most studied vaccines are the HyperAcute Pancreas vaccine (algenpantucel-L), the GVAX vaccine, and the DVAX vaccine [77]. Vaccine therapy has been well tolerated and had promising results. GVAX in combination with CRS-207, a live attenuated Listeria monocytogenes vector has been used as a second-line treatment for metastatic PC, and the combined arm has shown longer OS than GVAX (6.1 vs. 3.9 months, p = 0.02) [78]. Furthermore, a trial of the GVAX vaccine combined with radiotherapy and FOLFIRINOX is ongoing (NCT01595321). The vaccine algenpantucel-L stimulates a hyperacute reaction. A phase II study of the algenpantucel-L vaccine combined with chemoradiation has produced 1-year DFS and OS rates of 62% and 86%, respectively [79]. A phase III study of algenpantucel-L combined with chemotherapy has been also reported. Unfortunately researchers could not show any benefit in this clinical trial.