A phase I/II randomized trial using GM-CSF-producing and CD40L-expressing bystander cell line (GM.CD40L) vaccine in combination with CCL21 in stage IV lung adenocarcinoma: Preliminary results.

3091 Background: Our GM.CD40L vaccine (an allogeneic tumor cell-based vaccine generated from human bystander cell line) recruits and activates dendritic cells, which then migrate to regional lymph nodes, where T cell activation occurs, leading to systemic tumor cell killing. The CCL21 chemokine helps to recruit T cells and leads to enhanced T cell responses. The GM.CD40L.CCL21 combination has demonstrated additive effects in NSCLC mouse models. Methods: We initiated a phase I/II randomized study to evaluate GM.CD40L (Arm A) vs. GM.CD40L.CCL21 (Arm B) in patients with lung adenocarcinoma who had failed first-line therapy. Primary endpoints were safety and tolerability of Arm B in phase I and progression-free survival (PFS) in phase II; secondary endpoints included anti-tumor immune responses/T-cell responses by ELISpot assay on PBMC. Immune-related response criteria as determined by the investigator served to determine discontinuation from study treatment. Intradermal vaccines were administered every 14 days for 3 doses and then monthly X3. A two-stage minimax design was used. Results: In phase I, 3 patients received GM.CD40L.CCL21; no dose-limiting toxicities occurred. Between 4/2012 and 12/2012, Arm A enrolled 11 and Arm B enrolled 16 patients, including those in phase I (median age: 70/67.5 years, females: 45.5%/37.5%, PS1: 54.5%/75%, median prior regimens: 3/5 for Arm A vs. Arm B, respectively). Most common toxicities for Arm A vs. Arm B were injection site reaction (45.5%/43.8%), fatigue (9.1%/37.5%), anorexia (0%/12.5%), and pain in extremity (0%/12.5%). Median PFS for Arm A vs. B was 4.4 vs. 4.4 months (p=0.37). Of the 6 patients who remained on study post RECIST v1.1 progression, all demonstrated further progression on subsequent scans and were removed from the study. Of patients evaluable for efficacy, stable disease was 3/7 and progressive disease was 6/7 for Arm A vs. Arm B, respectively. Analyses of ELISpot assay on the PBMC are underway. Conclusions: GM.CD40L.CCL21 vaccine is well tolerated; thus far, median PFS results are similar to GM.CD40L vaccine. Updated results of the phase II trial will be presented. Clinical trial information: NCT01433172.

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Phase II Trial of a GM-CSF-producing and CD40L-expressing Bystander Cell Line Combined With an Allogeneic Tumor Cell–based Vaccine for Refractory Lung Adenocarcinoma

Journal of Immunotherapy ◽

10.1097/cji.0b013e3182a80237 ◽

2013 ◽

Vol 36 (8) ◽

pp. 442-450 ◽

Cited By ~ 13

Author(s):

Ben C. Creelan ◽

Scott Antonia ◽

David Noyes ◽

Terri B. Hunter ◽

George R. Simon ◽

...

Keyword(s):

Tumor Cell ◽

Lung Adenocarcinoma ◽

Cell Line ◽

Phase Ii ◽

Phase Ii Trial ◽

Bystander Cell ◽

Gm Csf ◽

Allogeneic Tumor ◽

Allogeneic Tumor Cell

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Safety and Immunogenicity of the Heterosubtypic Influenza A Vaccine MVA-NP+M1 Manufactured on the AGE1.CR.pIX Avian Cell Line

Vaccines ◽

10.3390/vaccines7010033 ◽

2019 ◽

Vol 7 (1) ◽

pp. 33 ◽

Cited By ~ 9

Author(s):

Pedro M. Folegatti ◽

Duncan Bellamy ◽

Amy Flaxman ◽

Catherine Mair ◽

Chris Ellis ◽

...

Keyword(s):

T Cell ◽

Phase I ◽

Cell Line ◽

Phase I Study ◽

Influenza A ◽

Seasonal Influenza ◽

T Cell Responses ◽

Influenza Vaccines ◽

Cell Mediated Immunity ◽

Cell Responses

Seasonal influenza infections have a significant global impact leading to increased health and economic burden. The efficacy of currently available seasonal influenza vaccines targeting polymorphic surface antigens has historically been suboptimal. Cellular immune responses against highly conserved Influenza A virus antigens, such as nucleoprotein (NP) and matrix protein-1 (M1), have previously been shown to be associated with protection from disease, whilst viral-vectored vaccines are an effective strategy to boost cell-mediated immunity. We have previously demonstrated that MVA encoding NP and M1 can induce potent and persistent T cell responses against influenza. In this Phase I study, we evaluated the safety and immunogenicity of MVA-NP+M1, which was newly manufactured on an immortalized cell line, in six healthy adult participants. The vaccine was well-tolerated with only mild to moderate adverse events that resolved spontaneously and were comparable to previous studies with the same vaccine manufactured in chick embryo fibroblasts. A significant increase in vaccine-specific T cell responses was detected seven days after immunization and was directed against both antigens in the vector insert. This small Phase I study supports progression of this vaccine to a Phase IIb study to assess immunogenicity and additional protective efficacy in older adults receiving licensed seasonal influenza vaccines.

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608 Immunodominant listeria epitopes compete with vaccine-directed cd8+ t-cell responses rescued by peptide-MHC stabilizing modifications

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0608 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A644-A644

Author(s):

John Flickinger ◽

Jagmohan Singh ◽

Yanki Yarman ◽

Robert Carlson ◽

Scott Waldman ◽

...

Keyword(s):

Listeria Monocytogenes ◽

T Cell ◽

Cell Line ◽

Mhc Class I ◽

T Cell Responses ◽

Cd8 T Cell ◽

Class I ◽

Peptide Ligand ◽

Altered Peptide Ligand ◽

Cell Responses

BackgroundThe Gram-positive bacterium Listeria monocytogenes (Lm) is a promising vector for cancer immunotherapy due to its ability to directly infect antigen-presenting cells, induce potent CD8+ T-cell immunity, and remodel immunosuppressive tumor microenvironments.1 Recent clinical trials have demonstrated safety and immunogenicity of Lm-based cancer vaccines in lung, cervical, pancreatic, and other cancers. In colorectal cancer, the transmembrane receptor guanylyl cyclase C (GUCY2C) is an emerging target for immunotherapy.2 Here, we examined the immunogenicity of a recombinant strain of Listeria monocytogenes secreting GUCY2C (Lm-GUCY2C). Surprisingly, Lm-GUCY2C vaccination induced robust Lm-specific CD8+ T-cell immunity but failed to prime GUCY2C-specific CD8+ T-cell responses. These studies explore the hypothesis that immunodominant Lm antigens suppress primary immunity to subdominant GUCY2C epitopes in Lm-GUCY2CMethodsLm-GUCY2C expresses the extracellular domain of mouse GUCY2C23-429 downstream of an ActA promoter integrated into the genome of the live, attenuated delta actA delta inlB Lm strain. Altered peptide ligands were designed based on NetMHCpan 4.0 peptide-MHC binding algorithms and similarly cloned into Lm. Peptide-MHC class I complex stability was quantified by FACS-based surface peptide-MHC dissociation on the TAP-deficient cell line, RMA-S H-2Kd.3In vivo efficacy studies employed IFNγ-ELISpot quantification of T-cell responses and tumor challenge studies with the CT26 colorectal cancer cell line. Adenovirus expressing GUCY2C was used as a positive control.2 4ResultsLm-GUCY2C vaccination of BALB/c mice generated Lm-specific CD8+ T-cell responses but an absence of GUCY2C-specific immunity. Peptide-MHC stability studies revealed poor stability of the dominant GUCY2C254-262 epitope complexed with H-2Kd compared to H-2Kd-restricted Lm epitopes derived from the LLO and p60 Lm antigens. Mutation of the GUCY2C254-262 peptide at critical anchoring residues for binding H-2Kd revealed that the altered peptide ligand with an F255Y mutation significantly improved the stability of the GUCY2C254-262-H-2Kd complex. Similarly, vaccination of mice with recombinant Lm-GUCY2C expressing the altered peptide ligand (Lm-GUCY2CF255Y) restored GUCY2C immunogenicity and antitumor immunity.ConclusionsImmunodominant Lm antigens may interfere with immune responses directed to the vaccine target antigen GUCY2C by competing with GUCY2C epitope for MHC class I binding and presentation. Moreover, use of a substituted GUCY2C -peptide ligand with enhanced peptide-MHC class I stability restored GUCY2C-specific immunity in the context of Lm-GUCY2C, an approach that can be translated to patients. Importantly, these studies also suggest that ongoing Lm-based vaccine development programs targeting a variety of antigens in other cancer types may be similarly limited by the immunodominance of Lm epitopes.AcknowledgementsThe authors thank Dr. Peter Lauer for providing the pPL2 integration vector used in cloning Lm-GUCY2C and Dr. Sean Murphy for providing the RMA-S H-2Kd cell line.Ethics ApprovalStudies were approved by the Thomas Jefferson University IACUC (Protocol # 01956).ReferencesFlickinger JC, Rodeck U, Snook AE. Listeria monocytogenes as a Vector for Cancer Immunotherapy: Current Understanding and Progress. Vaccines (Basel) 2018;6. doi:10.3390/vaccines6030048.Snook AE, Baybutt TR, Xiang B, Abraham TS, Flickinger JC, Hyslop T, et al. Split tolerance permits safe Ad5-GUCY2C-PADRE vaccine-induced T-cell responses in colon cancer patients. J Immunother Cancer 2019;7:104. doi:10.1186/s40425-019-0576-2.Müllbacher A, Lobigs M, Kos FJ, Langman R. Alloreactive cytotoxic T-cell function, peptide nonspecific. Scand J Immunol 1999;49:563–9.Flickinger J. JC, Singh J, Carlson R, Leong E, Baybutt T, Barton J, et al. Chimeric Ad5.F35 vector evades anti-adenovirus serotype 5 neutralization opposing GUCY2C-targeted antitumor immunity. J Immunother Cancer 2020.

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Phase II Randomized Study of Vaccine Treatment of Advanced Prostate Cancer (E7897): A Trial of the Eastern Cooperative Oncology Group

Journal of Clinical Oncology ◽

10.1200/jco.2004.08.083 ◽

2004 ◽

Vol 22 (11) ◽

pp. 2122-2132 ◽

Cited By ~ 167

Author(s):

Howard L. Kaufman ◽

Wei Wang ◽

Judith Manola ◽

Robert S. DiPaola ◽

Yoo-Joung Ko ◽

...

Keyword(s):

Prostate Cancer ◽

Clinical Trial ◽

T Cell ◽

Phase Ii ◽

Eastern Cooperative Oncology Group ◽

T Cell Responses ◽

Oncology Group ◽

Clinical Progression ◽

Cell Responses ◽

Antibody Titers

Purpose A phase II clinical trial was conducted to evaluate the feasibility and tolerability of a prime/boost vaccine strategy using vaccinia virus and fowlpox virus expressing human prostate-specific antigen (PSA) in patients with biochemical progression after local therapy for prostate cancer. The induction of PSA-specific immunity was also evaluated. Patients and Methods A randomized clinical trial was conducted by the Eastern Cooperative Oncology group and 64 eligible patients were randomly assigned to receive four vaccinations with fowlpox-PSA (rF-PSA), three rF-PSA vaccines followed by one vaccinia-PSA (rV-PSA) vaccine, or one rV-PSA vaccine followed by three rF-PSA vaccines. The major end point was PSA response at 6 months, and immune monitoring included measurements of anti-PSA and anti-vaccinia antibody titers and PSA-specific T-cell responses. Results The prime/boost schedule was well tolerated with few adverse events. Of the eligible patients, 45.3% of men remained free of PSA progression at 19.1 months and 78.1% demonstrated clinical progression-free survival. There was a trend favoring the treatment group that received a priming dose of rV-PSA. Although no significant increases in anti-PSA antibody titers were detected, 46% of patients demonstrated an increase in PSA-reactive T-cells. Conclusion Therapy with poxviruses expressing PSA and delivered in a prime/boost regimen was feasible and associated with minimal toxicity in the cooperative group setting. A significant proportion of men remained free of PSA and clinical progression after 19 months follow-up, and nearly half demonstrated an increase in PSA-specific T-cell responses. Phase III studies are needed to define the role of vaccination in men with prostate cancer or those who are at risk for the disease.

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