pepinemab (VX15)

The KEYNOTE-B84 study (NCT04815720) evaluated the safety and efficacy of pepinemab in combination with pembrolizumab as a first-line treatment for immunotherapy-naïve patients with R/M HNSCC. Biomarker studies conducted in patients with surgically resectable metastatic melanoma (NCT03769155) and HNSCC (NCT03690986) received neoadjuvant treatment with pepinemab/nivolumab/ipilimumab combinations compared to nivolumab or ipilimumab alone...Increased density and maturity of lymphoid aggregates correlated with disease control and longer progression-free survival (PFS). Conclusions Pepinemab, a Semaphorin 4D (SEMA4D) blocking antibody, in combination with ICB converts 'Cold' tumors to 'Hot' by inducing organized lymphoid aggregates.

Screening and on-treatment tumor biopsies were collected from several clinical trials: the KEYNOTE-B84 study (NCT04815720), that evaluated the safety and efficacy of pepinemab in combination with pembrolizumab as a first-line treatment for immunotherapy-naïve patients with R/M HNSCC, and biomarker neoadjuvant studies conducted in metastatic melanoma (NCT03769155) and HNSCC (NCT03690986) patients with surgically resectable disease treated with pepinemab/nivolumab/ipilimumab combinations compared to nivolumab or ipilimumab alone. When SEMA4D is blocked from binding to its receptors, suppression is reduced, leading to increased penetration and organization of antigen presenting cells (APC) and lymphoid cells in the tumor microenvironment. It is expected that this would facilitate interaction and communication among these cell populations, accounting for improved immune responses in otherwise "cold" tumors.

P1, N=28, Recruiting, H. Lee Moffitt Cancer Center and Research Institute | Trial completion date: Jul 2026 --> Dec 2026 | Trial primary completion date: Jul 2024 --> Dec 2024

P1/2, N=50, Completed, Vaccinex Inc. | Active, not recruiting --> Completed | Trial primary completion date: Jun 2023 --> Jun 2024

P1/2, N=26, Completed, Children's Oncology Group | Active, not recruiting --> Completed

P1/2 | "Results suggest that combination therapy induced formation of highly organized lymphoid aggregates in HNSCC tumors, with a high density of activated B cells, DC and T cells. Together with similar observations indicating that combination immunotherapy with pepinemab induces mature lymphoid structures in tumors of patients with metastatic melanoma, provides evidence of treatment-induced biologic activity corresponding with disease control and suggests a novel and independent mechanism of pepinemab to enhance immune interactions and ICI activity. Clinical trial information: NCT04815720."

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

P1, N=10, Completed, Emory University | Active, not recruiting --> Completed

P1, N=41, Active, not recruiting, Emory University | Trial completion date: Dec 2031 --> Dec 2032

P1/2, N=65, Recruiting, Vaccinex Inc. | Phase classification: P1b/2 --> P1/2 | Trial completion date: Sep 2023 --> Dec 2024 | Trial primary completion date: Sep 2023 --> Dec 2024

Patients must have failed first-line 5-fluorouracil or gemcitabine-based combination chemotherapy. To date, 7 patients have been enrolled (Clinical Trial NCT05102721). Clinical trial information: NCT05102721.

P1/2, N=26, Active, not recruiting, Children's Oncology Group | Trial completion date: Dec 2025 --> Sep 2024

P1, N=50, Recruiting, Emory University | Trial completion date: Jul 2023 --> Jul 2025 | Trial primary completion date: Jul 2023 --> Jul 2024

P1/2, N=50, Active, not recruiting, Vaccinex Inc. | Recruiting --> Active, not recruiting | Trial completion date: Feb 2024 --> Jun 2024 | Trial primary completion date: Dec 2023 --> Jun 2023

Pepinemab was well-tolerated and showed signs of anti-tumor activity in in immunotherapy-resistant and PD-L1 negative/low non-small cell lung cancer patients when combined with checkpoint inhibitor (avelumab)...HER2-specific T cells will be expanded ex vivo and subsequently infused to patients following lymphodepletion with cyclophosphamide...The primary objective is safety and tolerability; secondary objectives will include evaluation of T cell immunity and immune subsets, efficacy, PK/PD/ADA of pepinemab, and biomarker assessments. Clinical trial information: NCT05378464.

P1, N=41, Active, not recruiting, Emory University | Recruiting --> Active, not recruiting | Trial primary completion date: Dec 2022 --> Dec 2023

The combination of pepi/nivo/ipi is well-tolerated and provides robust and durable pathologic response. This therapy may act by fostering interactions between B and T cell populations within TLS and modulating myeloid cells. Pepi has the potential to augment the activity of CI in melanoma without additional toxicity.

P1, N=10, Active, not recruiting, Emory University | Trial completion date: Dec 2022 --> Dec 2024 | Trial primary completion date: Dec 2022 --> Dec 2023

Pepinemab was well-tolerated 2,3 and showed signs of anti-tumor activity in in immunotherapy-resistant, PD-L1 negative/low non-small cell lung cancer patients when combined with checkpoint inhibitor (avelumab)...HER2-specific T cells will be expanded ex vivo and subsequently infused to patients following lymphodepletion with cyclophosphamide...The primary objective is safety and tolerability; secondary objectives will include evaluation of T cell immunity and immune subsets, efficacy, PK/PD/ADA of pepinemab, and biomarker assessments. Trial Registration NCT05378464

P1, N=28, Recruiting, H. Lee Moffitt Cancer Center and Research Institute

P1, N=10, Active, not recruiting, Emory University | N=32 --> 10 | Recruiting --> Active, not recruiting

P1, N=36, Recruiting, Emory University | Trial primary completion date: Dec 2021 --> Dec 2022

P1b/2, N=80, Recruiting, Vaccinex Inc. | Initiation date: May 2021 --> Aug 2021

P1b/2, N=80, Recruiting, Vaccinex Inc. | Not yet recruiting --> Recruiting

The combination of pepinemab with avelumab was well tolerated in NSCLC and showed signs of antitumor activity in immunotherapy resistant and PD-L1 negative / low tumors.

P1b, N=62, Completed, Vaccinex Inc. | Active, not recruiting --> Completed | Trial completion date: May 2020 --> Sep 2020 | Trial primary completion date: May 2020 --> Sep 2020

Pts enrolled in this study were observed to have lower PD-L1 expression relative to prior single agent studies (likely due to approval of pembrolizumab for first line therapy)... This trial is nearing completion with only 5 of 62 subjects remaining on study. Preliminary data suggest the combination is well tolerated and shows signs of increased antitumor activity, particularly in PD-L1 negative or low tumors. Updated clinical response data and immunophenotypic analyses will be presented.

Among 29 evaluable IOF patients, 2 experienced confirmed partial response (PR) with 66% and 52% tumor reduction following acquired resistance to prior treatment with pembrolizumab, 15 additional patients experienced stable disease (SD), and at least 7 patients had durable clinical benefit of ≥ 23 weeks. Enrollment is complete and this interim analysis suggest the combination of pepinemab plus avelumab is well tolerated and shows initial clinical signals of antitumor activity. Updated clinical response data, as well as additional immunophenotyping of both inflammatory and suppressive myeloid cells will be presented.

These studies will provide the first integrated clinical assessment of the use of anti-SEMA4D antibody to reprogram the TME.

Patients with resectable stage IIIB/C/D melanoma were enrolled to control (no neoadjuvant therapy) or treatment cohorts (n = 8 in four cohorts of pepinemab plus nivolumab, ipilimumab, nivolumab/ipilimumab or alone). Neoadjuvant nivolumab and pepinemab results in increased T cell infiltration with excellent major response rate (38%) and expected safety profile. We continue to enroll patients using other rational combinations of pepinemab and CI. Research Funding: Vaccinex, Inc.

Among 29 evaluable IOF patients, two experienced confirmed partial response (PR) with 63% and 52% tumor reduction on study following acquired resistance to prior treatment with pembrolizumab, 15 additional patients experienced stable disease, and at least 5 patients with durable clinical benefit of ≥ 23 weeks. Interim analysis suggests the combination of pepinemab plus avelumab is well tolerated and shows initial clinical signals of antitumor activity. Updated clinical response data (minimum of 6 mo. follow-up), as well as additional immunophenotyping of both inflammatory and suppressive myeloid cells will be presented.

P1b, N=62, Active, not recruiting, Vaccinex Inc. | Recruiting --> Active, not recruiting