The earliest recognized biomarker of AD is deposition of Aβ amyloid that leads to formation of plaques and may, over time, trigger or at least be followed by gliosis/neuroinflammation and neurofibrillary tangles, accompanied by neurodegenerative changes including neuronal and synaptic loss. We have previously reported that semaphorin 4D (SEMA4D), the major ligand of plexin B receptors expressed on astrocytes, is upregulated in diseased neurons during progression of AD and Huntington’s disease (HD). Binding of SEMA4D to PLXNB receptors triggers astrocyte reactivity, leading to loss of neuroprotective homeostatic functions, including downregulation of glutamate and glucose transporters (doi:10.1186/s12974-022-02509-8), and gain of neurotoxic processes, including release of inflammatory mediators and further activation of phagocytic glia. Pepinemab, a high affinity, SEMA4D blocking antibody, demonstrated clinical benefit and was well tolerated in a completed Phase 2 study in early manifest HD (doi:10.1038/s41591-022-01919-8). Pepinemab prevented disease-associated metabolic decline in glucose uptake (FDG-PET) and significantly reduced levels of plasma GFAP, biomarkers of astrocyte reactivity. Importantly, pepinemab appeared to slow cognitive decline in HD by 36% (p=0.007), as determined by the HD Cognitive Assessment Battery composite score (2). The double-blind, placebo-controlled SIGNAL-AD (NCT04381468) study enrolled 50 individuals with MCI or mild AD dementia (MMSE 17-26) and amyloid positive status. Treatment was randomized 1:1 to pepinemab (40 mg/kg) or placebo (Q4W, IV infusion) for 12 months. The primary objective of the study is safety and tolerability, and key efficacy objective is evaluation of a biomarker for brain metabolic activity, FDG-PET imaging. Additional secondary and exploratory assessments include fluid biomarkers, plasma GFAP and pTau-217, and several validated, clinically meaningful cognitive scales (including CDR-SB, iADRS, ADAS-Cog13), as well as multiplex proteomics to evaluate neuroinflammatory activity. Topline data, including safety, brain metabolism (FDG-PET), fluid biomarkers of reactive astrocytes (GFAP), tau phosphorylation (p-tau 217), and inflammation, and potential treatment effects on cognitive decline will be presented. Given the many physiological parallels between glial activation and inflammatory processes in HD and AD, prior results from the SIGNAL-HD trial suggest that preventing astrocyte activation and reducing brain inflammation with pepinemab treatment could be an attractive alternative or complement to anti-Aβ antibodies.

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 .

Correlative biomarker analysis: 4A, Shift in balance of tumoral myeloid cells correlates with response. 4B, Baseline circulating AMC and ANC correlate with PFS 4C, High baseline circulating AMC:ALC is associated with disease progression and resistance to immunotherapy 4D, Baseline circulating PMN-MDSC in IOF and ION

This Supplementary Methods section provides details for assays that allowed elucidation of the pharmacokinetic and pharmacodynamic results described in the Results and Discussion sections of the article. These supplemental methods descriptions are to be published with the manuscript

Change from baseline in target lesion diameters: 3A, Spider plot of the change in the sum of target lesion diameters from baseline over time for evaluable immunotherapy naive patients (n=21). The lines are color coded based on best response; * pretracheal LN measured 8 mm at last scan resulting in a response of CR in the target lesion, but overall response of PR due to presence of non-target lesion. 3B, Spider plot of the change in the sum of target lesion diameters from baseline over time for evaluable immunotherapy failure patients (n=29). The lines are color coded based on best response.

This supplementary information file contains the Figure Legend for the Supplementary Figure S1. This figure legend and Supplementary Figure Fig S1 are intended for publication with the manuscript; Fig S1 shows the effect of VX15/2503 administration on serum levels of soluble SEMA4D. Article text related to Fig S1 is contained in the Results and Discussion sections, pages 19 and 22, respectively.

Background Immunosuppressive 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. 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 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. Results The 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. Conclusions The 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. References Clavijo 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-SITC2022.0613 Shafique 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-20–4792 Burtness 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 Approval This study was approved by WIRB Copernicus Group's Ethics Board; approval number 20210250.

PK/PD: Mean pepinemab serum concentrations for all patients dosed with 10mg/kg are presented in comparison to mean cellular SEMA4D levels (2A), total soluble SEMA4D levels (2B), and cellular SEMA4D receptor occupancy / saturation (2C). Cmax (2D) and AUC0-t (2E) is shown for each dose group as well as trough pepinemab levels at each 2 week Cycle (2F). PK parameters in D-F are reported as mean +/- SEM.

Total sSEMA4D levels for subjects in the 9 mg/kg dose cohort were measured in sera by ELISA and the data plotted versus study day. The data shown are representative of sSEMA4D results obtained with samples from subjects in other dose cohorts completing at least cycle 1. These data are intended for publication with the manuscript.

Pepinemab (VX15/2503) is a humanized IgG4 monoclonal antibody that blocks the binding of semaphorin 4D (SEMA4D) to its plexin receptors. SEMA4D is upregulated in neurons in response to stress and triggers activation of plexin-positive astrocytes with concomitant loss of normal astrocyte functions. Drivers of glial cell activation may represent important novel targets to modify progression of neurodegenerative pathology. Blocking antibody to SEMA4D has been shown to reduce neurodegenerative processes in preclinical models, including Huntington’s disease (HD) and Alzheimer’s disease (AD). SIGNAL-HD (NCT02481674), a completed Phase 2 trial, provided clinical rationale for the ongoing Phase 1/2 SIGNAL-AD study (NCT04381468). The SIGNAL-HD study included 301 subjects with late prodromal (LP) and early manifest (EM) HD. Subjects were treated with monthly infusions of pepinemab for at least 18 months and evaluated for safety and a variety of clinical parameters including cognition (HD-CAB). Imaging endpoints included structural MRI to assess brain atrophy and FDG-PET to assess brain metabolism. The SIGNAL-AD study plans to include 40 subjects with early AD treated for approximately 1 year, with objectives including safety, change in brain metabolism via FDG-PET, and clinical endpoints including cognition. In SIGNAL-HD, pepinemab was well-tolerated and was shown to cross the BBB to engage its target. Co-primary efficacy outcome measures did not achieve statistical significance in this study, however, positive trends in the direction of pepinemab benefit were observed and analysis of secondary and exploratory endpoints was therefore pursued. In 179 EM subjects, a treatment benefit was observed in 6/6 components of the HD-CAB cognitive assessment battery, with a significant treatment effect on HD-CAB composite score (p = 0.007). Further changes in prespecified exploratory imaging endpoints suggest that pepinemab treatment reduced brain atrophy (volumetric MRI) and slowed or reversed decline in metabolic activity in 26/26 brain regions, with 15/26 regions showing a significant positive treatment effect (p≤0.05) by FDG-PET imaging. SIGNAL-HD showed a favorable safety profile and positive trends in cognition and imaging endpoints that encourage continued development in both HD and AD. The Phase 1b/2a study in AD (SIGNAL-AD), is currently enrolling and initial safety review is planned for end of February.

e18033 Background: Immunosuppressive 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) promotes tumor infiltration and activation of DCs and CD8+ T cells and reverses immunosuppression, including attenuation of MDSC recruitment and function, leading to enhanced efficacy of ICIs. Pepinemab, a SEMA4D blocking antibody, in combination (combo) with avelumab provided clinical benefit in some patients with ICI-resistant and PD-L1-low NSCLC. Pembrolizumab (pembro) is approved as monotherapy or in combo with chemo for the first-line treatment of recurrent or metastatic (R/M) HNSCC, representative of a class of tumors that express higher levels of SEMA4D and MDSC. The primary hypothesis of this proof-of-concept study is that pepinemab in combo with pembro will yield increased clinical benefit compared to the reported activity for pembro monotherapy in R/M HNSCC. Methods: KEYNOTE-B84 (NCT04815720) is a single-arm open-label study evaluating the safety, efficacy, and PK/PD of pepinemab in combo with pembro as first-line treatment of R/M HNSCC. Subjects with measurable disease per RECIST1.1, ECOG 0 or 1, are eligible; subjects who have received prior ICIs or other systemic treatment for R/M HNSCC are excluded. The study includes a safety run-in (n = 3) and dose-expansion phase (maximum n = 62). Pepinemab, previously found to be well-tolerated in combo with other ICIs, will be evaluated initially at the highest intended dose of 20 mg/kg, in combo with 200 mg pembro, both administered i.v. Q3W. The dose expansion phase plans to include nearly equal distribution of subjects who have tumor PD-L1 combined positive scores (CPS) of < 20 and ≥20. The primary efficacy endpoint is ORR, and the secondary endpoints are PFS, DoR, and OS, as well as exploratory biomarker analyses. Pre- and on-treatment biopsies will be collected for evaluation of immune contexture in TME. Results: The safety run-in phase (n = 3) is complete, and the combo appeared to be well-tolerated with no DLTs observed; SMC approved continuation to dose expansion. Strikingly, two of the three patients have been observed to experience a complete response (CR). Biomarker analysis revealed that tumors in both responders expressed low levels of PD-L1 (CPS < 20). The third patient progressed prior to first scan, suffering several unrelated SAEs attributed to a pre-existing co-morbidity. Conclusions: The ongoing KEYNOTE-B84 study completed the initial safety run-in phase, with two of three subjects achieving CR. Phase 2 will evaluate pepinemab, a SEMA4D inhibitor, as a novel strategy to potentially overcome resistance and enhance activity of pembro in R/M HNSCC. Clinical trial information: NCT04815720.

SIGNAL is a multicenter, randomized, double-blind, placebo-controlled phase 2 study (no. NCT02481674) established to evaluate pepinemab, a semaphorin 4D (SEMA4D)-blocking antibody, for treatment of Huntington’s disease (HD). The trial enrolled a total of 265 HD gene expansion carriers with either early manifest (EM, n = 179) or late prodromal (LP, n = 86) HD, randomized (1:1) to receive 18 monthly infusions of pepinemab ( n = 91 EM, 41 LP) or placebo ( n = 88 EM, 45 LP). Pepinemab was generally well tolerated, with a relatively low frequency of serious treatment-emergent adverse events of 5% with pepinemab compared to 9% with placebo, including both EM and LP participants. Coprimary efficacy outcome measures consisted of assessments within the EM cohort of (1) a two-item HD cognitive assessment family comprising one-touch stockings of Cambridge (OTS) and paced tapping (PTAP) and (2) clinical global impression of change (CGIC). The differences between pepinemab and placebo in mean change (95% confidence interval) from baseline at month 17 for OTS were −1.98 (−4.00, 0.05) (one-sided P = 0.028), and for PTAP 1.43 (−0.37, 3.23) (one-sided P = 0.06). Similarly, because a significant treatment effect was not observed for CGIC, the coprimary endpoint, the study did not meet its prespecified primary outcomes. Nevertheless, a number of other positive outcomes and post hoc subgroup analyses—including additional cognitive measures and volumetric magnetic resonance imaging and fluorodeoxyglucose–positron-emission tomography imaging assessments—provide rationale and direction for the design of a phase 3 study and encourage the continued development of pepinemab in patients diagnosed with EM HD.

Background T cell receptor (TCR)-based therapeutics have displayed clinical proof-of-concept, however challenges remain to robustly identify both novel targets and therapeutically active TCRs against endogenous targets. Methods Here, we have developed a multi-plexed platform to efficiently identify novel TCRs towards non-mutated, tumor specific targets. We have developed a functional expansion protocol, combined with single cell sequencing, that enables the discovery of diverse TCRs in both function and sequence to multiple targets simultaneously. Results These novel TCRs are highly sensitive, with sub-nanomolar EC50s. Furthermore, these novel TCRs display in vitro killing of target-bearing cells. To interrogate the specificity of these TCRs, we utilized 3T-TRACE, a highly diverse pHLA-target library platform to identify potential cross-reactive peptides that could identify potential liabilities pre-clinically. We find that although sequence distinct TCRs display the same on-target reactivity, they vary considerably in their cross-reactivity. Conclusions Altogether, we have developed a robust platform to identify and select therapeutically active TCRs for TCR-T based therapy.

Background T cell engagers (TCEs) are bi-functional biologics that bind a target on tumor cells and the CD3 of the TCR-complex on T cells to induce immune-mediated killing of tumors expressing the epitope of interest. While most TCEs on the market and in development target cell surface antigens with tumor- or lineage-specific expression, this approach cannot exploit the tumor-specific expression of intracellular proteins, which make up the majority of the human proteome. However, peptides derived from virtually all intracellular proteins are presented on the cell surface by Human Leukocyte Antigen (HLA) and can be targeted therapeutically to exploit the tumor-specific expression of intracellular proteins. A key safety concern for therapeutics targeting peptide-HLA complexes is cross-reactivity, as unintended binding of peptides expressed on healthy tissues can lead to lethal off-target toxicity. Methods Here, we utilize Athebody® DARPins (Designed Ankyrin Repeat Proteins), engineered proteins based on an ankyrin repeat scaffold, to generate highly specific binders against an epitope from the cancer-germline antigen MAGE-A4 bound to HLA-A2. Using our proprietary 3T-TRACE™ platform, we perform a global cross-reactivity assessment to identify potential off-target liabilities, many of which are sequence-dissimilar to the intended MAGE-A4 epitope and would therefore be undetectable by traditional methods. The interplay of this cross-reactivity risk evaluation, informing tailored binder selection, allowed us to identify leads of unparalleled efficiency and safety profiles. TCEs armed with these Athebody® DARPins induce high potency killing of MAGE-A4-expressing cancer cell lines with no detectable killing of antigen-negative cells. We further tune the format of these molecules to retain high killing activity while minimizing cytokine release, a key determinant of dose-limiting toxicity in the clinic. Conclusions These optimized TCEs express at high titers and display a favorable developability profile. The work presented here demonstrates a novel approach to develop TCEs with excellent potency and specificity against tumor-restricted intracellular targets.

Background The SEMA4D:plexin B1/B2 signaling pathway triggers reactive astrogliosis in the CNS. Stressed neurons upregulate SEMA4D and astrocytes intimately associated with neurons express both plexin B1 and B2 receptors. Binding of SEMA4D to those receptors results in astrogliosis including characteristic morphogenetic changes and downregulation of metabolic activity and recycling of neurotransmitters (Evans, et al., SEMA4D is upregulated in neurons of diseased brains and triggers astrocyte reactivity. Journal of Neuroinflammation, In press). Others have shown that the SEMA4D:plexin pathway is also involved in crosstalk between astrocytes and microglia (Clark, et al., Barcoded viral tracing of single-cell interactions in central nervous system inflammation. Science 372 (2021)), hence SEMA4D plays a central role in overall glial activation. Aims We predicted that treatment with SEMA4D blocking antibody should prevent reactive transformation of astrocytes and reduce the associated decline in brain metabolic activity that is characteristic of HD progression. We investigated the impact of treatment on the course of motor and cognitive decline during clinical progression. Methods FDG-PET was employed in the SIGNAL study to detect reversal of metabolic decline in most brain ROI in early manifest (EM) HD subjects (Feigin, et al., Pepinemab antibody blockade of SEMA4D in early Huntington’s Disease: the randomized, placebo-controlled, phase 2 SIGNAL trial. Nature Medicine, In press). Motor activity was evaluated by UHDRS-TMS and Q-Motor assessments. A subset of two components of HD-CAB, OTS and PTAP, constituted a cognitive family and the full HD-CAB was retained as an exploratory cognitive endpoint. Results Decline in glucose utilization observed in the placebo group was prevented and partially reversed by SEMA4D blockade with pepinemab. While the largest metabolic decline is observed in striatum in HD, a similar treatment effect was not observed for FDG-PET SUVR in caudate and putamen of either EM or late prodromal (LP) subjects. Since degeneration of medium spiny neurons in striatum is an early event in prodromal HD that continues following motor diagnosis, this could account for reduced glucose utilization that is not SEMA4D-dependent. Nevertheless, since caudate atrophy is significantly inhibited by pepinemab following 18 months of treatment, it appears that a SEMA4D-dependent mechanism becomes active during continuing disease progression. In keeping with the absence of a treatment effect on metabolic activity in striatum, we also did not observe an effect on early motor dysfunction as detected by either UHDRS-TMS or Q-Motor assessments. Importantly, in parallel with metabolic effects in multiple cortical regions, several other endpoints indicated an impact of treatment on a key cognitive domain related to learning in early manifest disease. The timing of SEMA4D-dependent cognitive and functional treatment outcomes is consistent with the complex kinetics of neuroinflammatory responses by glial cells. Conclusions In contrast to Alzheimer’s disease for which the Clinical Dementia Rating (CDR) scale and ADAS-cognitive subscale are well-established as meaningful composite and cognitive endpoints respectively, there is not an established measure of cognition in HD that is currently accepted as intrinsically meaningful by US and EU regulators. We suggest that direct measures of learning could constitute an intrinsically meaningful cognitive endpoint in manifest HD.

Purpose: Immunosuppressive 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) promotes tumor infiltration and activation of DCs and CD8+ T cells and reverses immunosuppression, including attenuation of MDSC recruitment and function, leading to enhanced efficacy of ICIs. Pepinemab, a humanized SEMA4D blocking antibody, in combination (combo) with avelumab provided clinical benefit in some patients with ICI-resistant and PD-L1-low NSCLC. Pembrolizumab (pembro) is approved as monotherapy or in combo with chemo for the first-line treatment of recurrent or metastatic (R/M) HNSCC. More effective treatments are, however, needed to increase the frequency and duration of responses. The primary hypothesis of this proof-of-concept study is that pepinemab in combo with pembro will yield increased clinical benefit compared to the reported activity for pembro monotherapy in R/M HNSCC. Methods: KEYNOTE B84 (NCT04815720) is a multicenter, single-arm open-label study evaluating the safety, efficacy, and PK/PD of pepinemab in combo with pembro as first-line treatment of R/M HNSCC. Subjects with measurable disease per RECIST1.1, ECOG PS of 0 or 1, and PD-L1 CPS ≥ 0 are eligible; subjects who have received prior ICIs or other systemic treatment for R/M HNSCC are excluded. The study includes a safety run-in (n=3) and dose-expansion phase (maximum n=62). Pepinemab, previously found to be well-tolerated in combo with other ICIs, will be evaluated initially at the highest intended dose of 20 mg/kg, in combo with 200 mg pembro, both administered i.v. Q3W. The dose expansion phase will include an equal distribution of subjects who have tumor PD-L1 combined positive scores (CPS) of <20 and ≥20. The primary efficacy endpoint is ORR, and the secondary endpoints are PFS, DoR, and OS, as well as exploratory biomarker analyses. Pre- and on-treatment biopsies will be collected for evaluation of immune contexture in TME. Results: The safety run-in phase (n=3) was successfully completed. The combo was well tolerated with no DLTs observed. One of the three patients had a confirmed complete response, a second patient progressed with several SAEs attributed to comorbidities (diabetes) deemed unrelated to treatment, and the third patient has not yet completed tumor evaluation. The safety monitoring committee has recommended that the dose-expansion phase be initiated at 20 mg/kg pepinemab and 200 mg pembro Q3W. Conclusions: The ongoing KEYNOTE B84 study completed the initial safety run-in phase. Phase 2 will evaluate pepinemab, a SEMA4D inhibitor, as a novel strategy to potentially overcome resistance and enhance activity of pembro in R/M HNSCC. Citation Format: Terrence L. Fisher, Elizabeth E. Evans, Crystal Mallow, Amber Foster, Megan Boise, Ernest Smith, John E. Leonard, Marya F. Chaney, J. Thaddeus Beck, Steven Hager, Nabil F. Saba, Conor Steuer, Douglas Adkins, Barbara Burtness, Maurice Zauderer. Phase 1/2 study of pepinemab, an inhibitor of semaphorin 4D, in combination with pembrolizumab as first-line treatment of recurrent or metastatic head and neck cancer (KEYNOTE B84) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT111.

Background Immunosuppressive myeloid cells in the tumor microenvironment (TME) are a critical limitation to the efficacy of immune checkpoint inhibitors (ICIs) in patients with head and neck squamous cell carcinoma (HNSCC). Both semaphorin 4D (SEMA4D, CD100) and MDSCs are reported to play important roles in the growth and progression of HNSCC. Preclinical and clinical data demonstrated that antibody blockade of SEMA4D promotes tumor infiltration and activation of dendritic cells and CD8+ T cell, reverses immunosuppression, including attenuation of MDSC recruitment and function, and leading to enhanced efficacy of ICIs.1 2 In a study evaluating pepinemab, a humanized SEMA4D blocking antibody, in combination with avelumab in patients with non-small cell lung cancer, the combination appeared to provide clinical benefit in patients with difficult to treat ICI-resistant and PD-L1-low tumors.3 Pembrolizumab is approved as first line therapy as monotherapy or in combination with chemotherapy in recurrent or metastatic (R/M) HNSCC, however not all patients respond to ICIs and require more effective treatments. Methods KEYNOTE B84 (NCT04815720) is a multicenter, single-arm open-label study to evaluate the safety, efficacy, PK/PD of pepinemab in combination with pembrolizumab in subjects with locally advanced, R/M HNSCC. Subjects with measurable disease per RECIST1.1 will be enrolled, including oropharynx, oral cavity, hypopharynx and larynx, and ECOG PS of 0 or 1. Subjects who have received prior ICIs are excluded. This study will include a Safety Run-in phase (n=3–18) and a Dose Expansion (maximum n=62) phase. Pepinemab, which is well-tolerated in combination with other ICIs, will be evaluated starting with the highest intended dose of 20 mg/kg, in combination with 200 mg pembrolizumab, both administered intravenously every 3 weeks. The Dose Expansion phase will include an even distribution of subjects who have combined positive scores of <20 and ≥20. The primary efficacy endpoint is ORR, and secondary endpoints include DOR, OS, PFS, as well as exploratory biomarker analysis. Pre- and on-treatment biopsies will be collected for evaluation of immune contexture in TME. Results Screening has been initiated at several of a planned total of 18 sites. Multiplex immunohistochemistry (IHC) panels have been established to phenotype cells in the TME, including CD8+ T cells, DCs, MDSCs, Tregs, monocytes, macrophages. Conclusions There remains a clear unmet need for more effective immunomodulatory treatment options to overcome immunosuppressive factors in the TME. The KEYNOTE B84 study will evaluate pepinemab as a potential treatment option to overcome resistance to and enhance activity of pembrolizumab in HNSCC. Trial Registration NCT04815720 References Clavijo 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. Evans EE, Jonason AS Jr, Bussler H, Torno S, Veeraraghavan J, Reilly C, Doherty MA, Seils J, Winter LA, Mallow C, Kirk R, Howell A, Giralico S, Scrivens M, Klimatcheva K, Fisher TL, Bowers WJ, Paris M, Smith ES, Zauderer M. Antibody Blockade of Semaphorin 4D Promotes Immune Infiltration into Tumor and Enhances Response to Other Immunomodulatory Therapies. Cancer Immunol Res 2015 Jun;3(6):689–701. Shafique MR, Fisher TL, Evans EE, Leonard JE, Pastore DRE, Mallow CL, Smith E, Mishra V, Schröder A, Chin KM, Beck JT, Baumgart MA, Govindan R, Gabrail NY, Spira AI, Seetharamu N, Lou Y, Mansfield AS, Sanborn RE, Goldman JW, Zauderer M. A Phase Ib/II Study of Pepinemab in Combination with Avelumab in Advanced Non-Small Cell Lung Cancer. Clin Cancer Res 2021 Jul 1;27(13):3630–3640. Ethics Approval This study was approved by WIRB Copernicus Group's Ethics Board on 11Feb2021; approval number 20210250.

Abstract Falls are a common and costly concern for older adults. Digital technologies can offer new, inexpensive approaches to increase access and engagement with falls prevention programmes. Keep-On-Keep-Up is a personalised, falls prevention App with strength and balance exercises plus health literacy games. This study reports on the user-centred design, usability testing and implementation of the KOKU App. Older adults aged 55 years and older in the UK were invited to take part in the study. Data collection included focus groups; baseline and 6 week questionnaires and assessments; semi-structured interviews and one focus group with falls prevention therapists to explore App usability. Thirty older adults were invited to use KOKU unsupervised, 3 times a week for 6 weeks. Data were analysed using thematic content analysis. Focus groups (n=11) with 66 older users and 11 therapists informed development. Thirty older adults (mean age = 75) were recruited for the in-depth testing. Mean SUS score was 71 indicating high usability. Qualitative themes included: ease of use (app usability; iPad properties; exercise presentation), usefulness (physical/psychological benefits; falls education), attitude towards the App and intention to use (technological barriers; flexibility of use; exercise class versus App). Therapists (n=6) viewed the KOKU platform positively and suggested extensions for further progression. No adverse events were reported during the study. This research demonstrates that KOKU is an acceptable and easy to use falls prevention intervention that facilitates older adults’ ability to access falls prevention training at a time, and in a location, that suits them.