Vaccinex (United States)

Middle East respiratory syndrome coronavirus (MERS-CoV) was identified as a human pathogen in 2012 and causes ongoing sporadic infections and outbreak clusters. Despite case fatality rates (CFRs) of over 30% and considerable pandemic potential, a safe and efficacious vaccine has not been developed. Here we report the design, characterization, and preclinical evaluation of MERS-CoV antigens. Our lead candidate comprises a stabilized spike displayed on a self-assembling ferritin nanoparticle that can be produced from a high-expressing, stable cell pool. This vaccine elicits robust MERS-CoV pseudovirus and authentic virus neutralizing antibody titers in BALB/c mice. Immunization of male non-human primates (NHPs) with one dose of Alhydrogel-adjuvanted vaccine elicited a > 103 geometric mean titer of pseudovirus neutralizing antibodies that was boosted with a second dose. Sera from these NHPs exhibited cross-reactivity against spike-pseudotyped lentiviruses from MERS-CoV clades A, B, and C as well as a distant pangolin merbecovirus. In human DPP4 transgenic mice, immunization provided dose-dependent protection against MERS-CoV lethal challenge, and in an established alpaca challenge model using female alpacas, immunization fully protected against MERS-CoV infection. This MERS-CoV nanoparticle vaccine is a promising candidate for clinical advancement to protect at-risk individuals and for future use in a potential outbreak setting.

Summary Middle East respiratory syndrome coronavirus (MERS-CoV) was first identified as a human pathogen in 2012 and causes ongoing sporadic infections and outbreak clusters. Despite case fatality rates (CFRs) of over 30% and the pandemic potential associated with betacoronaviruses, a safe and efficacious vaccine has not been developed for prevention of MERS in at-risk individuals. Here we report the design, in vitro characterization, and preclinical evaluation of MERS-CoV antigens. Our lead candidate comprises a stabilized spike ectodomain displayed on a self-assembling ferritin nanoparticle that can be produced from a high-expressing, stable cell pool. This vaccine elicits robust antibody titers in BALB/c mice as measured by MERS- CoV pseudovirus and live-virus neutralization assays. Immunization of non-human primates (NHPs) with a single dose of Alhydrogel-adjuvanted vaccine elicits >10 3 geometric mean titer (GMT) of pseudovirus neutralizing antibodies that can be boosted with a second dose. These antibody levels are durable, with GMTs that surpass the post-prime levels for more than 5 months post-boost. Importantly, sera from these NHPs exhibit broad cross-reactivity against lentiviruses pseudotyped with spike proteins from MERS-CoV clades A, B, and C as well as a more distant pangolin merbecovirus. In transgenic mice expressing human DPP4, immunization provided dose-dependent protection against MERS-CoV lethal challenge, and in an established alpaca challenge model, immunization fully protected against MERS-CoV infection. This protein-based MERS-CoV nanoparticle vaccine is a promising candidate for advancement to clinical development to protect at-risk individuals and for future use in a potential outbreak setting.

2603 Background: Myeloid cells contribute to suppression of adaptive immunity within the TME and limit the efficacy of immune checkpoint inhibitors (ICIs) in head and neck squamous cell carcinoma (HNSCC). Semaphorin 4D (SEMA4D) signaling through its receptors (PlexinB1/B2, CD72) promotes recruitment and suppressive function of myeloid suppressor cells (MDSC). In preclinical and clinical studies, SEMA4D antibody blockade attenuated MDSC and increased penetration and organization of dendritic cells (DC) and T cells into tertiary lymphoid structures that enhanced activity of ICI. We hypothesize that SEMA4D blocking antibody pepinemab may regulate infiltration and crosstalk of immune cells in TME as a novel and complementary mechanism of immune enhancement when combined with immune checkpoint therapy. Methods: KEYNOTE-B84 (NCT04815720) is an ongoing single-arm open-label study evaluating the safety, efficacy, and PK/PD of pepinemab in combination with pembrolizumab as first-line treatment of recurrent or metastatic HNSCC. Exploratory biomarker analyses were performed to evaluate spatial interactions of tumoral immune cells. Pre- and on-treatment tumor biopsies were collected and assessed by multiplex immunohistochemistry for up to 36 biomarkers/biopsy. Unbiased algorithms identified co-localization of markers for advanced cell phenotyping, density, spatial and proximity analysis. Biomarker results were then stratified by demographic and clinical outcome measures. Results: An increase in activated APC (HLA-DR+CD11c+ and HLA-DR+CD68+) and reduced density of MDSC (Arg1+CD14+ and ARG1+CD15+) was observed in patients with durable disease control. Interestingly, spatial analysis of tumor biopsies revealed that combination therapy induced the formation of highly organized immune aggregates, including a high density of activated B cells, DCs, CD4+ and CD8+ T cells, including stem-like CD8+TCF1+PD1+ T cells. Presence of immune aggregates increased in on-treatment compared to pre-treatment biopsies, even in HPV-negative and PD-L1 low tumors. Favorable spatial interactions between DC-1, CD8, CD4, and B cells was associated with PFS and disease control. Conclusions: 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 .

Abstract Background The WHO estimated that in 2022 49% of people affected by Mpox were PLWH. Due to initial vaccine shortage in 2022, a 1/5 dose of vaccine given intradermally (ID) was FDA-authorized (8/9/22). The ID regimen had never been evaluated in PLWH. Here we describe the characteristics, and IgG responses of Mpox vaccination in PLWH and HIV-negative participants. Methods We are conducting a longitudinal, observational study of adults with and without HIV who received the JYNNEOS vaccine or had Mpox infection in NYC. Clinical, demographic information, and Mpox H3L-specific serum IgG titers are assessed. Results 145 participants are enrolled: 25% are PLWH (median CD4 685 cells/mm3), 14% had Mpox disease and 21% had prior smallpox vaccination. 71% with Mpox disease were PLWH. The cohort is racially/ethnically diverse, mostly men (81%) and LGBTQ+ (90%). A third of the participants were recruited from NYC DOHMH pop-up vaccination site (34%), followed by peer or professional referral (20% & 19%). Routes of vaccination were: SC-ID (49%), ID-ID (21%), SC-SC (20%), and ID-SC (10%). Redness (37%) & swelling (21%) at site of injection were common reactions. Prior smallpox vaccination was associated with higher and sustained IgG titers even after one vaccine dose. Excluding such participants, antibody titers start declining post-dose 2 (antibody half-life of 103 days). There was no difference in IgG titers at 3 months post-dose 2 between PLWH and HIV-negative for ID or any other route. Titers at 3 months post-dose 2 in PLWH correlated with CD4 counts. Longer interval between the two doses contributed to higher titers. Mpox infection yielded to significantly higher titers than vaccination post-dose 1, but no after 2 doses. Conclusion Our study highlights the disproportionate burden of Mpox infection on PLWH. A diverse population representative of those most affected by 2022 Mpox was recruited. The vaccine, whether ID or SC, was well tolerated in PLWH and HIV-negative. More than two-thirds of participants with Mpox disease were PLWH. Individuals with prior smallpox vaccination maintain strong antibody levels post-dose 2, however, levels decline in individuals with no anterior prime. Our preliminary results show no negative impact of the ID dose regimen on antibody levels in PLWH. Disclosures Ellie Carmody, MD, MPH, AstraZeneca: Stocks/Bonds|Merck: Stocks/Bonds Lalitha Parameswaran, MD, MPH, Pfizer: Grant/Research Support Mark J. Mulligan, M.D., Lilly: Grant/Research Support|Meissa Vaccines, Inc.: Advisor/Consultant|Meissa Vaccines, Inc.: Board Member|Merck: Advisor/Consultant|Merck: Board Member|Pfizer: Advisor/Consultant|Pfizer: Board Member|Pfizer: Grant/Research Support|Sanofi: Grant/Research Support

BackgroundImmunosuppressive myeloid cells in the tumor microenvironment (TME) limit the efficacy of immune checkpoint inhibitors (ICIs) in head and neck squamous cell carcinoma (HNSCC). Preclinical and clinical studies demonstrated that antibody blockade of semaphorin 4D (SEMA4D) reverses immunosuppression, including attenuation of MDSC recruitment and function1 and promotes organization of lymphoid aggregates within tumors,2 leading to enhanced efficacy of ICIs. Pepinemab, a SEMA4D blocking antibody, in combination with avelumab was well tolerated and provided clinical benefit in patients with ICI-resistant, PD-L1-low NSCLC.3 The primary hypothesis of this proof-of-concept study is that pepinemab in combination with pembrolizumab will improve the efficacy of immunotherapy in R/M HNSCC.MethodsKEYNOTE-B84 (NCT04815720) is an ongoing single-arm open-label study evaluating the safety, efficacy, and PK/PD of pepinemab in combination with pembrolizumab as first-line treatment of R/M HNSCC. The study includes immunotherapy naïve patients who have tumor PD-L1 combined positive scores (CPS) of <20 and ≥20 with an interim analysis when 36 patients complete the first tumor response assessment. The primary efficacy endpoint is ORR, and secondary endpoints include PFS, DoR, and OS, as well as exploratory biomarker analyses. Pre- and on-treatment biopsies are collected for evaluation of immune contexture in TME. Data presented here include pre-specified interim analysis of safety, efficacy, and biomarker assessments.ResultsThe combination appears to be well tolerated with no DLTs observed or safety signals identified by the SMC. Notably, in the PD-L1 low population (CPS<20, N=19), we observed approximately a doubling in ORR, DCR, and PFS for the combination of pepinemab and pembrolizumab, as compared to reported single agent pembrolizumab.4 Among the CPS<20 population, ORR was 21.1% (2 CR and 2 PR), DCR was 73.7%, and median PFS was 5.79 months. In contrast, in the CPS≥20 subgroup, the ORR was 17.6% (n=17), similar to ICI monotherapy for this population. Spatial multiplex IHC analysis of pre- and post-treatment tumor biopsies demonstrated an increase in activated APC, reduced recruitment of MDSC, and highly organized immune aggregates (figure 1) that corresponded with disease control.ConclusionsThe pre-specified interim analysis of the ongoing KN-B84 study showed that pepinemab in combination with pembrolizumab was well-tolerated, suggested early signs of improved anti-tumor response over single agent pembrolizumab in the difficult to treat PD-L1 low group, and provided evidence of treatment-induced biomarker changes in the TME of responder tumors, including formation of high-density lymphoid aggregates.ReferencesClavijo PE, Friedman J, Robbins Y, Moore EC, Smith E, Zauderer M, Evans EE, Allen CT. Semaphorin4D Inhibition Improves Response to Immune-Checkpoint Blockade via Attenuation of MDSC Recruitment and Function. Cancer Immunol Res. 2019 Feb;7(2):282–291. doi: 10.1158/2326–6066.CIR-18–0156.Olson B, Mallow C, Reilly C, et al. 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. Journal for ImmunoTherapy of Cancer 2022;10:doi: 10.1136/jitc-2022-SITC2022.0613Shafique MR, Fisher TL, Evans EE, et al. A Phase Ib/2 Study of Pepinemab in Combination with Avelumab in Advanced Non-Small Cell Lung Cancer. Clin Cancer Res 2021, doi: 10.1158/1078–0432.CCR-20–4792Burtness B, Rischin D, Greil R, Soulières D, Tahara M, et al. Pembrolizumab Alone or With Chemotherapy for Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma in KEYNOTE-048: Subgroup Analysis by Programmed Death Ligand-1 Combined Positive Score. J Clin Oncol. 2022 Jul 20;40(21):2321–2332. doi: 10.1200/JCO.21.02198.Ethics ApprovalThis study was approved by WIRB Copernicus Group’s Ethics Board; approval number 20210250. 676 Figure 1Treatment induced improved balance of activated APC and MDSC and presence of highly organized immune aggregates consisting of high density of B cells, DC and T cell zones, and stem- like CD8, and correlate with disease control. (A, B) Representative images of on-treatment biopsies. (C) B cell density/aggregate, each dot represents one aggregate. CR: complete response SD: stable disease, PD: progressive disease.

Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines have shown efficacy against SARS-CoV-2, it is unknown if coronavirus vaccines can also protect against other coronaviruses that may infect humans in the future. Here, we show that coronavirus vaccines elicited cross-protective immune responses against heterologous coronaviruses. In particular, we show that a severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) vaccine developed in 2004 and known to protect against SARS-CoV-1 conferred robust heterologous protection against SARS-CoV-2 in mice. Similarly, prior coronavirus infections conferred heterologous protection against distinct coronaviruses. Cross-reactive immunity was also reported in patients with coronavirus disease 2019 (COVID-19) and in individuals who received SARS-CoV-2 vaccines, and transfer of plasma from these individuals into mice improved protection against coronavirus challenges. These findings provide the first demonstration to our knowledge that coronavirus vaccines (and prior coronavirus infections) can confer broad protection against heterologous coronaviruses and establish a rationale for universal coronavirus vaccines.

10061 Background: SEMA4D has broad immunomodulatory effects in the tumor microenvironment (TME); blocking SEMA4D in combination with checkpoint inhibitors (CI) promotes immune infiltration, reduces recruitment of myeloid cells, enhances T cell activity, and promotes tumor regression. We hypothesized that adding pepinemab (VX15/2503), which targets SEMA4D, to CI would increase immunomodulatory effects and augment response in melanoma (NCT03769155). Methods: 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). Here we report results from patients receiving two doses of nivolumab (360mg) and pepinemab (15mg/kg) every three weeks followed by surgery. Primary endpoint was T cell infiltration into the TME; secondary endpoints include pathologic response rates, peripheral immune profile, and safety. Results: Ten patients are reported: two were controls, eight received neoadjuvant therapy. Two patients had pathologic complete response, one had a near-complete pathologic response ( &lt; 1% viable tumor), one had a partial response (41% viable tumor) and four had stable disease (73-90% viable tumor). All neoadjuvant patients underwent surgery without delay; one patient experienced grade 3 post-operative cellulitis. There were two treatment-related grade 3 adverse events (weakness and arthralgia). Pharmacodynamic studies confirmed saturation of PD-1 and SEMA4D in peripheral and tumor-infiltrating T cells. T/B cell (CD8+/CD20+) ratios, a surrogate for T cell infiltration, were higher in post-treatment tumors compared to pre-treatment and were higher in the tumor bed compared to normal adjacent tissue. Flow cytometric evaluation identified an increase in CD26hi CD4+ and CD8+ tumor-infiltrating effectors in treated patients compared to controls and an increase in peripheral frequencies of the PD-1-responsive effector HLA-DR+CD38+Ki67+ CD4+ and CD8+ T cells following treatment. Treatment increased infiltration of myeloid populations into the TME, increased expression of PD-L1 on TME myeloid populations, and increased expression of the SEMA4D receptor Plexin-B2 on the surface of TME CD45− and M2 macrophages and MDSC. Conclusions: 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. Clinical trial information: NCT03769155.

Abstract Background: Blockade of the PD/PD-L1 pathway is an effective immunotherapy for NSCLC, however rational combination therapies are needed to overcome resistance mechanisms. VX15/2503 (pepinemab) is an IgG4 humanized monoclonal antibody targeting semaphorin 4D (SEMA4D, CD100). In vivo preclinical models demonstrated antibody blockade of SEMA4D promoted immune infiltration and reduced function and recruitment of immunosuppressive myeloid cells within the tumor. Importantly, preclinical combinations of anti-SEMA4D with various immunotherapies enhanced T cell activity and tumor regression. Avelumab is a fully human IgG1 antibody specific for PD-L1 and has been approved for both Merkel cell and urothelial carcinomas. The CLASSICAL-Lung clinical trial tests the combination of pepinemab with avelumab to couple immune activation via checkpoint inhibition with beneficial modifications of the immune microenvironment via pepinemab. Here, we present interim results of the dose escalation portion of the CLASSICAL-Lung study. Methods: This Phase Ib/II, open label, single arm, first-in-human combination study is designed to evaluate the safety, tolerability and efficacy of pepinemab in combination with avelumab in 62 subjects with advanced (IIIB/IV) NSCLC. The trial is split into dose escalation (n=12) and dose expansion (n=50) phases. The dose escalation portion includes patients who are immunotherapy naïve and have either progressed or declined standard first or second-line systemic anticancer therapy. The expansion phase includes a similar patient cohort as well as a second cohort of patients whose tumors progressed during or following immunotherapy. Patients in the dose escalation cohorts received ascending doses of pepinemab (5, 10, 20 mg/kg, Q2W) in combination with avelumab (10mg/kg, Q2W). The primary objective of dose escalation is safety, tolerability, and identification of the RP2D for dose expansion. Secondary objectives include evaluation of efficacy, immunogenicity, and PK/PD, and an exploratory objective is to identify candidate biomarkers of activity. Results / Conclusions: Dose escalation was successfully completed. The combination was found to be well tolerated at all dose levels tested and the RP2D was selected as 10mg/kg pepinemab Q2W (with 10mg/kg avelumab Q2W) for the dose expansion phase. No concerning safety signals have been identified to date. The most frequent related AEs were grades 1 or 2 fatigue, pyrexia, or chills; no grade 3 AE occurred in more than one subject. One DLT, a grade 3 pulmonary embolism occurred in the 10mg/kg pepinemab cohort, resolved and did not recur in that same subject or additional subjects in any cohort. The disease control rate to date in all dose escalation patients treated for at least two months is 90%. More detailed data from the dose escalation cohorts will be presented, as well as an enrollment update for the dose expansion phase. Clinical trial information: NCT03268057 Citation Format: Michael Shafique, Terrence L. Fisher, Elizabeth E. Evans, John E. Leonard, Desa Rae Pastore, Crystal Mallow, Ernest Smith, Maurice Zauderer, Andreas Schröeder, Kevin Chin, Thaddeus Beck, Megan Baumgart, Rachel E. Sanborn, Jonathan W. Goldman. Interim results from CLASSICAL-Lung, a Phase Ib/II study of VX15/2503 (pepinemab) in combination with avelumab in advanced NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT086.

Background: Blockade of the PD/PD-L1 pathway is an effective immunotherapy for NSCLC, however rational combination therapies are needed to overcome resistance mechanisms. VX15/2503 (pepinemab) is an IgG4 humanized monoclonal antibody targeting semaphorin 4D (SEMA4D, CD100). In vivo preclinical models demonstrated antibody blockade of SEMA4D promoted immune infiltration and reduced function and recruitment of immunosuppressive myeloid cells within the tumor. Importantly, preclinical combinations of anti-SEMA4D with various immunotherapies enhanced T cell activity and tumor regression. Avelumab is a fully human IgG1 antibody specific for PD-L1 and has been approved for both Merkel cell and urothelial carcinomas. The CLASSICAL-Lung clinical trial tests the combination of pepinemab with avelumab to couple immune activation via checkpoint inhibition with beneficial modifications of the immune microenvironment via pepinemab. Here, we present interim results of the dose escalation portion of the CLASSICAL-Lung study.Methods: This Phase Ib/II, open label, single arm, first-in-human combination study is designed to evaluate the safety, tolerability and efficacy of pepinemab in combination with avelumab in 62 subjects with advanced (IIIB/IV) NSCLC. The trial is split into dose escalation (n=12) and dose expansion (n=50) phases. The dose escalation portion includes patients who are immunotherapy naïve and have either progressed or declined standard first or second-line systemic anticancer therapy. The expansion phase includes a similar patient cohort as well as a second cohort of patients whose tumors progressed during or following immunotherapy. Patients in the dose escalation cohorts received ascending doses of pepinemab (5, 10, 20 mg/kg, Q2W) in combination with avelumab (10mg/kg, Q2W). The primary objective of dose escalation is safety, tolerability, and identification of the RP2D for dose expansion. Secondary objectives include evaluation of efficacy, immunogenicity, and PK/PD, and an exploratory objective is to identify candidate biomarkers of activity.Results / Conclusions: Dose escalation was successfully completed. The combination was found to be well tolerated at all dose levels tested and the RP2D was selected as 10mg/kg pepinemab Q2W (with 10mg/kg avelumab Q2W) for the dose expansion phase. No concerning safety signals have been identified to date. The most frequent related AEs were grades 1 or 2 fatigue, pyrexia, or chills; no grade 3 AE occurred in more than one subject. One DLT, a grade 3 pulmonary embolism occurred in the 10mg/kg pepinemab cohort, resolved and did not recur in that same subject or additional subjects in any cohort. The disease control rate to date in all dose escalation patients treated for at least two months is 90%. More detailed data from the dose escalation cohorts will be presented, as well as an enrollment update for the dose expansion phase.Clinical trial information: NCT03268057Citation Format: Michael Shafique, Terrence L. Fisher, Elizabeth E. Evans, John E. Leonard, Desa Rae Pastore, Crystal Mallow, Ernest Smith, Maurice Zauderer, Andreas Schröeder, Kevin Chin, Thaddeus Beck, Megan Baumgart, Rachel E. Sanborn, Jonathan W. Goldman. Interim results from CLASSICAL-Lung, a Phase Ib/II study of VX15/2503 (pepinemab) in combination with avelumab in advanced NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT086.

e21519 Background: Semaphorins regulate tumor progression, immune responses, and angiogenesis. SEMA4D was identified as a candidate proto-oncogene by a Sleeping Beauty forward genetic screen that induced osteosarcoma in mice. SEMA4D is expressed on tumors, including osteosarcoma, and in the tumor microenvironment. VX15/2503, a humanized IgG4 monoclonal antibody, binds SEMA4D, blocks receptor interaction and enhances the anti-tumor immune response in preclinical studies. This trial aimed to determine the tolerability and recommended dose of VX15/2503 in patients with relapsed/refractory solid tumors and activity in patients with osteosarcoma. Methods: Part A enrolled patients age≤ 21y with refractory solid tumors to assess the tolerability of VX15/2503 (20 mg/kg) IV every 14 days x 2 doses/cycle. The recommended dose was one that was tolerated and achieved sustained target saturation. Up to 6 additional children were enrolled to assess pharmacokinetics (PK). In part B, a two-stage design was used to assess the activity of VX15/2503 in patients with measurable, relapsed /refractory osteosarcoma. In part B1 patients &gt; 21-30y accrued concurrently with part A; Part B2 (patients £ 21y) was initiated after the pediatric recommended dose was determined. Correlative studies including target saturation by VX15/2503 were required. Results: 18 eligible patients enrolled, 16 evaluable for toxicity. In part A (n = 12) the median (range) age was 12.5 (1-20) y. Diagnoses included osteosarcoma (8), neuroblastoma (2), other (2). No dose limiting toxicities (DLTs) were observed. In Part B1, (n = 6) median (range) age was 22.5 (22-30) y; one patient had cycle 1 DLTs (grade 3 acute kidney injury, creatinine increase, arthralgia and myalgia); a second patient had a later cycle DLT (grade 4 pericardial effusion). Given only 1/18 had a cycle 1 DLT, this did not impact dose selection. T-cell saturation by VX15/2503 was adequate and sustained in all patients. Conclusions: VX15/2503 was well tolerated at 20 mg/kg IV every 2 weeks and is the recommended dose in children, adolescents and young adults. The activity in osteosarcoma is under evaluation. Future trials combining VX15/2503 with novel agents are in development. Clinical trial information: NCT03320330.