On November 10, 2022 Vaccinex, Inc. (Nasdaq: VCNX), a clinical-stage biotechnology company pioneering a differentiated approach to treating cancer and neurodegenerative diseases through the inhibition of semaphorin 4D (SEMA4D), and its collaborators at Emory University and the Moffitt Cancer Center reported that two abstracts, including an oral presentation and a poster related to investigator-sponsored trials for pepinemab combinations, are being presented at The Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)’s (SITC) (Free SITC Whitepaper) 37th Annual Meeting (Press release, Vaccinex, NOV 10, 2022, View Source [SID1234623675]).

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These studies describe novel biomarkers of response and resistance to immunotherapy that inform new potential treatment options in combination with Vaccinex’s pepinemab antibody.

Oral Presentation of pepinemab combinations with immune checkpoint blockade for neoadjuvant treatment of Stage III melanoma:
Dr. Brian Olson of Winship Cancer Institute at Emory University presented results of a collaborative study with Vaccinex investigating biomarkers and benefit of neoadjuvant combination immunotherapy including Vaccinex’s pepinemab antibody in patients with resectable Stage III melanoma who went on to receive adjuvant therapy with nivolumab after surgery (NCT03769155). 100% of patients who received the triple combination of pepinemab, nivolumab and ipilimumab were recurrence free at 24 months. This contrasted with recurrence free survival of less than 40% in patients who received the dual combination of pepinemab and nivolumab or pepinemab and ipilimumab.

Importantly, it was observed that the LAG-3 immune checkpoint is increased on T cells in tumors from the subset of patients who did not respond to the combination of pepinemab plus nivolumab. This provides a strong rationale for a triple combination treatment with pepinemab and inhibitors of both the PD-1 and LAG-3 checkpoint pathways. Further characterization of the tumors resected from these patients demonstrated that combination treatments that include pepinemab give rise to highly organized lymphoid structures consisting of B lymphocytes in close proximity to activated CD8+ and CD4+ T cells. These organized lymphoid structures are believed to provide an environment that supports efficient differentiation of immunoprotective as opposed to immunosuppressive cells.

Poster Presentation of pepinemab combination with adoptive cell therapy for patients with HER2+ metastatic breast cancer:
The important role of CD4+ T cells in directing a productive immune response was also the rationale for an independent adoptive cell therapy trial in breast cancer presented by collaborators, Dr. Hyo S. Han and Dr. Brian Czerniecki of the Moffitt Cancer Center (NCT05378464). In preclinical studies, it was shown that SEMA4D antibody blockade in combination with a dendritic cell vaccine improved trafficking of dendritic cells to tumors and stimulated expansion of tumor-specific B and T cells, resulting in improved regression of both primary and distant tumors. A Phase 1/2 trial involving combination of pepinemab and trastuzumab with a dendritic cell vaccine followed by adoptive transfer of expanded autologous CD4+ T cells is now enrolling patients with HER2+ metastatic breast cancer.

Maurice Zauderer, Ph.D., President and Chief Executive Officer of Vaccinex, remarked, "The investigator-sponsored collaborative studies reported at SITC (Free SITC Whitepaper) 2022 provide safety information and describe novel biomarkers of response and resistance to immunotherapy that inform new potential treatment options in combination with Vaccinex’s pepinemab antibody. We plan to explore such strategies with partners interested in rational combinations to enhance the activity of their drugs through an independent mechanism of action, without notable additional toxicity."

Dr. Zauderer concluded, "Vaccinex is conducting a Phase 1b/2 study in patients with pepinemab in combination with KEYTRUDA for recurrent and metastatic head and neck squamous cell cancer (R/M HNSCC), the KEYNOTE-B84 study. We have previously reported promising initial results from this study, including complete responses in patients with difficult to treat tumors that express low levels of PD-L1. These exciting data build on our understanding of the potent activity of pepinemab in orchestrating and amplifying immune responses in combinations with companion immunotherapies. We continue to observe strikingly improved responses in this patient population and expect to report results of interim analysis from this study in 1Q 2023."

Oral Presentation Details:

"Neoadjuvant SEMA4D blockade with nivolumab alters suppressive myeloid cells while elevating B cell and CD26hi T cell infiltration in the tumors of patients with resectable stage III melanoma".

Abstract number: 613
Presentation Date/Time: Friday November 11 at 5:20 PM, EST
Session: 210: Cancer Surgery in the Age of Immunotherapy
Presenter: Dr. Brian Olson of Winship Cancer Institute at Emory University

This Phase 1 open label integrated biomarker study was designed to evaluate immune responses in tumor and blood before and after neoadjuvant treatment with immunotherapy combinations (n=8) compared to standard of care surgery without treatment (n=6). Objectives included biomarker correlates, as well as safety and tolerability in the neoadjuvant setting, and clinical response in terms of pathologic response and recurrence-free survival (RFS). In September 2022, Dr. Michael Lowe from the Emory team presented the clinical safety and efficacy data at the 2022 ESMO (Free ESMO Whitepaper) Congress in Paris, France, reporting that pepinemab enhanced RFS of nivolumab and ipilimumab combinations, yet was well-tolerated and did not enhance toxicities associated with the companion immune checkpoint blockade (ICB) drugs (1). At SITC (Free SITC Whitepaper), Dr. Olson reports the biomarker correlates of this study.

The first of several important findings is that LAG3 expression appears to be an escape mechanism to treatment with the combination of pepinemab plus nivolumab. LAG3 was significantly upregulated on CD8+ and CD4+ T cells in patients who experienced recurrence of cancer within 24 months of treatment, while LAG3 remained low in patients who were recurrence-free. Together with previously reported preclinical data demonstrating dramatic synergy of blocking antibodies to SEMA4D and LAG3, as well as the favorable safety profiles for both pepinemab and LAG-3 antibodies in clinical studies, this provides rationale to evaluate combinations of pepinemab with LAG3 and PD-1/PD-L1 targeted therapies.

Secondly, results demonstrate a striking increase in the formation of tertiary lymphoid structures (TLS) in tumors of patients responding to treatment with combination therapies that include pepinemab, but not single agent nivolumab. These highly organized TLS consist of activated and proliferating B cells surrounded by activated (CD69+) CD8+ and CD4+ T cells. Notably, a significant increase in CD26high CD4+ T cells was induced in all pepinemab combinations, especially in the highly effective triple combination. These cells were previously described by team member, Dr. Chrystal Paulos, to have enhanced multi-functionality, a rich profile of cytokine and chemokine secretion, and, importantly, long-term persistence and memory with improved cytotoxic function and activity in preclinical models of adoptive cell therapy (2, 3). This suggests that addition of pepinemab to adoptive cell and/or CAR-T therapies may more effectively augment or rescue anti-tumor immune responses in patients.

Poster Presentation Details:

"Phase I Study of Adoptive T Cell Therapy Following HER2-Pulsed Dendritic Cell Vaccine and Pepinemab/Trastuzumab in Patients with Metastatic HER2-Positive Breast Cancer (NCT05378464)".

Abstract number: 645
Presentation Date/Time: Thursday November 10 at 9:00 AM, EST
Session: Clinical Trials In Progress
Presenter: Dr. Hyo Han of Moffitt Cancer Center

Co-authors from Moffitt Cancer Center and Vaccinex present a newly initiated and actively enrolling trial to evaluate safety and efficacy of a combination therapy involving treatment with pepinemab/trastuzumab/DC-1 dendritic cell vaccine, followed by collection, expansion, and adoptive transfer of CD4+ Th1 cells in patients with trastuzumab-refractory metastatic breast cancer. Primary endpoints include safety and tolerability, with additional assessments of clinical efficacy as well as immune biomarkers in the tumors and blood.

About Pepinemab
Pepinemab is a humanized IgG4 monoclonal antibody that inhibits SEMA4D, which regulates chronic inflammation in the tumor microenvironment. Preclinical and clinical data show that pepinemab promotes infiltration/activation of dendritic cells/ CD8+ T-cells and reverses immunosuppression within the tumor (4,5).

Results of a Phase 1b/2 study to evaluate the combination of pepinemab with checkpoint inhibitor, BAVENCIO (avelumab, Merck KGaA) were presented at ASCO (Free ASCO Whitepaper) 2020 and were highlighted in the July 2021 publication of Clinical Cancer Research. Vaccinex reported that results of this Phase 1b/2 CLASSICAL-Lung trial showed a 25-33% Overall Response Rate (ORR) for patients with difficult to treat PD-L1 low/negative tumors treated with the combination. The study report also indicated that pepinemab did not increase immune-related toxicities of BAVENCIO but increased penetration of cytotoxic T cells (6). The publication is available electronically at: Clinical Cancer Research.

Vaccinex has global commercial and development rights to pepinemab, and is sponsor of the KEYNOTE-B84 study which is being performed in collaboration with Merck Sharp & Dohme Corp, a subsidiary of Merck and Co, Inc. Kenilworth, NJ, USA. Additional information about the study is available at: View Source
KEYTRUDA is a registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co. Inc., Kenilworth, NJ, USA.