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SEMA4D Antibody Blockade Overcomes Mechanisms of Immune

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SEMA4D Antibody Blockade Overcomes Mechanisms of Immune SEMA4D antibody blockade overcomes mechanisms of immune suppression and combination immunotherapy including TGFβ blockade promotes efficient tumor regression P478 Elizabeth E. Evans, Terrence L. Fisher, Crystal Mallow, Holm Bussler, Sebold Torno, Desa Rae Pastore, Alan Howell, Luis Ruffolo*, Nicholas Ullman*, Benjamin Dale*, Brian Belt*, Joe Bucukovski, Christine Reilly, Ernest Smith, David C. Linehan, Maurice Zauderer. Vaccinex and *University of Rochester, Rochester, New York [email protected] Summary Immune Checkpoint Combinations TGFβ Combinations CLASSICAL-Lung Phase 1/2b Trial: Combination with Avelumab Phase 1b Phase 2 Background: Despite progress of immune checkpoint blockade therapies, resistance A. Colon26: anti-CTLA-4 Combination C. Colon26: anti-LAG3 Combination This ongoing completely enrolled phase 1b/2, open label, single arm, first-in- mechanisms including myeloid suppression and upregulation of TGFβ signaling prevent human combination study is designed to evaluate the combination of Dose Escalation Dose Expansion durable clinical benefit in many cancer patients. Anti-semaphorin 4D (SEMA4D, CD100) pepinemab with avelumab in 62 subjects (pts) with advanced (stage IIIB/IV) blocking antibody promotes immune infiltration, reduces immunosuppression, and (n=12) (n=50) enhances T cell activity in the tumor microenvironment (TME), resulting in increased NSCLC. tumor control when combined with various immunotherapies in preclinical models (1-3). pepinemab + 10 mg/kg avelumab, Q2W Clinical trials of immune checkpoint inhibitors (ICI) in combination with pepinemab (VX15/2503), a humanized anti-SEMA4D antibody (4,5), are currently underway in Study Design IO Naive • several cancer indications. The trial is split into dose escalation (n=12) and dose expansion (n=50) phases. • Methods: Activity of anti-SEMA4D antibody in combination with immune checkpoint The dose escalation portion includes subjects who are immunotherapy naïve and have 5 mg/kg IO Failure inhibitors and TGFβ blockade was evaluated in preclinical mouse tumor models. Ongoing either progressed or declined standard first or second-line systemic anticancer therapy. • (n=3) clinical trials of immune checkpoint inhibitors (ICI) in combination with pepinemab Subjects in the three dose escalation cohorts received ascending doses of pepinemab (5, 10 mg/kg include: (i) a Phase 1b/2a combination trial of pepinemab with avelumab in ICI naïve or B. MOC1 HNSCC: anti-CTLA-4 Combo D. MColon26:ean Col2 6anti 15-oPDnc-118 Combination2 PD 10, 20 mg/kg, Q2W) in combination with avelumab (10mg/kg, Q2W). (n=32) • The expansion phase includes an IO naïve (ION) cohort as well as a second cohort of 10 mg/kg ICI refractory or relapsed NSCLC (CLASSICAL-Lung) (NCT03268057, N=65); (ii) 3 Control m subjects whose tumors progressed during or following immunotherapy (IO failure, IOF). (n=6) neoadjuvant integrated biomarker trials in patients with metastatic melanoma m 1000 aSEMA4D 0.3423 0.0307 IO Naive e Study Objectives (NCT03769155, n=36), metastatic colorectal, pancreatic (NCT03373188, n=32) and head m u aPD-1 + CTRL 0.0599 l • The primary objective is safety, tolerability, and identification of the RP2D for dose 10 mg/kg o and neck (NCT03690986, n=36) cancers treated with pepinemab in combination with v 0.0030 r aPD-1 + aSEMA4D expansion. 20 mg/kg nivolumab or ipilimumab. o 500 (n= 18) m * u • Secondary objectives include evaluation of efficacy, immunogenicity, and PK/PD, and an (n=3) T Results: Anti-SEMA4D antibody enhanced tumor regression when combined with n a exploratory objective is to identify candidate biomarkers of activity antibodies targeting CTLA-4, PD-1, PD-L1, LAG3, and TGFβ in several preclinical models. e M For example, anti-SEMA4D plus anti-TGFβ treatment resulted in maximal tumor growth 0 delay (TGD) of 239% (p<0.01) and 10/15 complete tumor regressions (CR) (p<0.05), 0 20 40 60 80 See POSTER P414 ENROLLMENT COMPLETE compared to 10% TGD and 0/13 CR with single agent anti-TGFβ or 29% TGD and 1/10 CR Day of Study with anti-SEMA4D alone in MC38 colon carcinoma model. Additionally, the combination Immunomodulatory effects of SEMA4D blockade can enhance immune checkpoint therapies. A,C,D. Colon26 (500,000 cells) were Immunomodulatory effects of SEMA4D blockade can enhance TGFβ blockade. A) Colon26 (500,000 cells) were subcutaneously of anti-SEMA4D, folfirinox, and ICI improved survival in KP2-tumor bearing mice, a KPC- subcutaneously implanted into Balb/c mice, that were then treated with αSEMA4D / MAb67 (10 mg/kg, weekly IP X4), αLAG3/C9B7W implanted into Balb/c mice, that were then treated with αSEMA4D / MAb67 (10 mg/kg, weekly IP X4) and αTGFβ/Mab1D11.16.8 (5 derived pancreatic adenocarcinoma model of immune exclusion, myeloid suppression (10 mg/kg 2x/week X4; n=20); αCTLA-4 / MAb UC10-4F10 (100/50/50 µg, q3 days; n=20), αPD-1 / MAb RMP1-14 (10 mg/kg, Integrated Biomarker Window of Opportunity Clinical Study mg/kg, 2x/week IP); n=15. B) MC38 (80,000 cells) were subcutaneously implanted into C57Bl/6 mice, that were then treated with and active TGFb signaling. In clinical trials, pepinemab was well-tolerated and analysis of twice/week, starting on day10, n=20), B. MOC1 HNSCC (5x106 cells) were subcutaneously implanted into C57Bl/6 mice, that were αSEMA4D/MAb67 (10 mg/kg, weekly IP) and αTGFb/Mab1D11.16.8 (10 mg/kg, 3x/week IP); n=15. pre and on-treatment biopsies revealed increased CD8 density and reduced presence of then treated with αSEMA4D/MAb67 (10 mg/kg, weekly IP), αCTLA-4 / MAb 9H-10 (5 mg/kg, q5D); n=10. In collaboration with Winship Cancer Institute, Emory University myeloid derived suppressor cells within TME. Conclusions: SEMA4D antibody blockade modulates the TME to enhance anti-tumor Anti-SEMA4D enhances T cell infiltration and Pepinemab facilitates T cell infiltration into Resectable PDAC immunity and combination therapies further enhance anti-tumor activity and overcome reduces immunosuppressive M2 TAM in immune excluded MSS metastatic CRC Anti-SEMA4D Mab neutralizes SEMA4D barrier at tumor TGFβ driven, highly desmoplastic and Fixed Time Point Tumor Weights Fixed Time Point CD8s Fixed Time Point TAMs Resectable HNSCC (n=16) important resistance mechanisms. Preliminary data suggest the combination of p=0.16 Resectable melanoma 0.4 ✱ ✱ immune excluded pancreatic cancer model P=0.16 (n=36) CRC resectable liver ✱ (n=36) pepinemab plus immune checkpoint therapy is well tolerated and shows initial signals of 20 40 No treatment Pepinemab ) mets (n=16) g margin and shifts the balance of tumor immunity 5 (6). A) C57b/6 mice were injected 0.3 ( 4 Currently enrolled:12 Currently enrolled: 10 antitumor activity in patients. Ongoing analysis of various therapeutic combinations and t 15 D 30 h 5 C / g 4 i orthotopically with KP2 cells* (derived from I Currently enrolled: 5 I D e TGFb1 TGFb2 TGFb3 C 0.2 C immunophenotyping of tissue biopsies will shed light on mechanism of action of w / H r 10 8 20 CRC, 1 PDAC o the spontaneous KRASG12D; TP53Flox/Wt; 4000 M 250 1000 A. Sema4D B. Increased infiltration of pro-inflammatory APC C. Shift in balance of tumor D + m C 0 SEMA4D antibody blockade in several combination therapies. u Normal 8 / T 0.1 gradient and CD8+ T cells immunity in TME P48-Cre autochthonous tumors from David 5 4 10 200 800 3500 F liver No treatment (SOC) No Treatment (SOC) Denardo, Washington University) and treated 150 600 No treatment (SOC) 0.0 0 0 t t 3000 e t D t le D n l in 4 in le t D t with αSEMA4D / MAb67, αPD1/MAb RMP1- c in 4 i ic o o c in 4 in i o a o h p A p i o A o Counts h Counts Vessel h e k M k Counts 100 p p 400 e p m p V c E c e k M k k e k e S e V c E c V c c h e S e e S e h h h h h C C Tumor Tumor-specific Cytotoxic T Cells 14, αCTLA-4 / MAbUC10-4F10 (10 mg/kg, 2500 + C C C C * = P<0.05 D + VX15/2503 (20 mg/kg) + 4 50 D 200 D A 4 Anti-SEMA4D Mab blocks binding to its cognate receptors 4 M A Vehicle a ICB + Vehicle E anti-SEMA4DM + ICB Bed VX15/2503 (15 mg/kg) twice weekly IP). Tumors were harvested m anti-SEMA4DS + Vehicle E e S %CD3+CD8+ IFNg ELISPOT S 2000 0 0 CTRL SEMA CTLA COMBO CTRL SEMA CTLA COMBO CTRL SEMA CTLA COMBO & receptor-mediated signaling activity Tumor after 2 weeks of treatment, weighed and VX15/2503 (20 mg/kg) VX15/2503 (20 mg/kg) dissociated for flow cytometric analysis of -1.05X 1.17X* 1.15X 1.18X 1.22X 1.09X 1.17X -1.02X -1.24X* p=0.432 p=0.014 p=0.181 p=0.301 p=0.178 p=0.51 p=0.143 p=0.824 p=0.06 VX15/2503 (15 mg/kg) Ipilimumab (1 mg/kg) • Promotes infiltration of potent APC and T cells into TME Ig Control CD8+ T cells and M2 TAM. Ipilimumab (3 mg/kg) VX15/2503 (20 mg/kg) • Inhibits function of MDSC, M2 TAM and Treg Anti-SEMA4D enhances expression of TGFbRII. Upregulation of TGF receptor Nivolumab (480 mg) VX15/2503 (20 mg/kg) TGFbRI TGFbRII VX15/2503 (20 mg/kg) Ipilimumab (1 mg/kg) SEMA4D CD11c F4/80 CD8 may result from down-regulation of its ligand, or upregulation5000 of an independent 8000 * * Nivolumab (480 mg) 67 4000 Nivolumab (480 mg) immune resistance mechanism. Upregulation of TGFbRII is associated with APC- 6000 M2-TAM MDSC independent and fibroblast-dependent resistance to3000immune checkpoint therapy VX15/2503 (15 mg/kg) VX15/2503 (20 mg/kg) 4000 Nivolumab (3 mg/kg) Counts (7).
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