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Poster: Presented at the 34th Annual Meeting of the Society for Immunotherapy of Cancer (SITC). SEMA4D antibody blockade overcomes mechanisms of immune suppression and combination immunotherapy including TGFβ blockade promotes efficient tumor regression

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11/09/2019 | 02:14 pm

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

eevans@vaccinex.com

Reilly, Ernest Smith, David C. Linehan, Maurice Zauderer.

Vaccinex and *University of Rochester, Rochester, New York

Summary

Immune Checkpoint Combinations

TGFβ Combinations

CLASSICAL-Lung Phase 1/2b Trial: Combination with Avelumab

Background: Despite progress of immune checkpoint blockade therapies, resistance mechanisms including myeloid suppression and upregulation of TGFβ signaling prevent durable clinical benefit in many cancer patients. Anti-semaphorin 4D (SEMA4D, CD100) blocking antibody promotes immune infiltration, reduces immunosuppression, and enhances T cell activity in the tumor microenvironment (TME), resulting in increased tumor control when combined with various immunotherapies in preclinical models (1-3). Clinical trials of immune checkpoint inhibitors (ICI) in combination with pepinemab (VX15/2503), a humanized anti-SEMA4D antibody (4,5), are currently underway in several cancer indications.

Methods: Activity of anti-SEMA4D antibody in combination with immune checkpoint inhibitors and TGFβ blockade was evaluated in preclinical mouse tumor models. Ongoing clinical trials of immune checkpoint inhibitors (ICI) in combination with pepinemab include: (i) a Phase 1b/2a combination trial of pepinemab with avelumab in ICI naïve or ICI refractory or relapsed NSCLC (CLASSICAL-Lung) (NCT03268057, N=65); (ii)

C.

A. Colon26: anti-CTLA-4 Combination

Colon26: anti-LAG3 Combination

B.

D.

MOC1 HNSCC: anti-CTLA-4 Combo

Colon26: anti-PD-1 Combination

This ongoing completely enrolled phase 1b/2, open label, single arm, first-inhuman combination study is designed to evaluate the combination of pepinemab with avelumab in 62 subjects (pts) with advanced (stage IIIB/IV)

NSCLC.

Study Design

  • The trial is split into dose escalation (n=12) and dose expansion (n=50) phases.
  • The dose escalation portion includes subjects who are immunotherapy naïve and have either progressed or declined standard first or second-line systemic anticancer therapy.
  • Subjects in the three dose escalation cohorts received ascending doses of pepinemab (5, 10, 20 mg/kg, Q2W) in combination with avelumab (10mg/kg, Q2W).
  • The expansion phase includes an IO naïve (ION) cohort as well as a second cohort of

Phase 1b

Phase 2

Dose Escalation

Dose Expansion

(n=12)

(n=50)

pepinemab + 10 mg/kg avelumab, Q2W

IO Naive

5 mg/kg

IO Failure

(n=3)

10 mg/kg

10 mg/kg

(n=32)

neoadjuvant integrated biomarker trials in patients with metastatic melanoma (NCT03769155, n=36), metastatic colorectal, pancreatic (NCT03373188, n=32) and head and neck (NCT03690986, n=36) cancers treated with pepinemab in combination with nivolumab or ipilimumab.

Results: Anti-SEMA4D antibody enhanced tumor regression when combined with antibodies targeting CTLA-4,PD-1,PD-L1, LAG3, and TGFβ in several preclinical models. For example, anti-SEMA4D plus anti-TGFβ treatment resulted in maximal tumor growth delay (TGD) of 239% (p<0.01) and 10/15 complete tumor regressions (CR) (p<0.05), compared to 10% TGD and 0/13 CR with single agent anti-TGFβ or 29% TGD and 1/10 CR with anti-SEMA4D alone in MC38 colon carcinoma model. Additionally, the combination

3

Control

mm

1000

aSEMA4D

0.3423

0.

volume

aPD-1 + CTRL

0.0599

aPD-1 + aSEMA4D

0.0030

Mean Tumor

500

*

0

0

20

40

60

80

Day of Study

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

subjects whose tumors progressed during or following immunotherapy (IO failure, IOF).

Study Objectives

  • The primary objective 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

See POSTER P414

(n=6)

IO Naive

20 mg/kg

10 mg/kg

(n= 18)

(n=3)

ENROLLMENT COMPLETE

of anti-SEMA4D, folfirinox, and ICI improved survival in KP2-tumor bearing mice, a KPC- derived pancreatic adenocarcinoma model of immune exclusion, myeloid suppression and active TGFb signaling. In clinical trials, pepinemab was well-tolerated and analysis of pre and on-treatment biopsies revealed increased CD8 density and reduced presence of myeloid derived suppressor cells within TME.

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

(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,

mg/kg, 2x/week IP); n=15. B) MC38 (80,000 cells) were subcutaneously implanted into C57Bl/6 mice, that were then treated with

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.

then treated with αSEMA4D/MAb67 (10 mg/kg, weekly IP), αCTLA-4 / MAb 9H-10 (5 mg/kg, q5D); n=10.

Integrated Biomarker Window of Opportunity Clinical Study

In collaboration with Winship Cancer Institute, Emory University

Conclusions: SEMA4D antibody blockade modulates the TME to enhance anti-tumor immunity and combination therapies further enhance anti-tumor activity and overcome important resistance mechanisms. Preliminary data suggest the combination of pepinemab plus immune checkpoint therapy is well tolerated and shows initial signals of antitumor activity in patients. Ongoing analysis of various therapeutic combinations and immunophenotyping of tissue biopsies will shed light on mechanism of action of SEMA4D antibody blockade in several combination therapies.

Anti-SEMA4D Mab blocks binding to its cognate receptors

    • receptor-mediatedsignaling activity
  • Promotes infiltration of potent APC and T cells into TME
    • Inhibits function of MDSC, M2 TAM and Treg

FORWARD LOOKING STATEMENT: To the extent that statements contained in this presentation are not descriptions of historical facts regarding Vaccinex, Inc. ("Vaccinex," "we," "us," or "our"), they are forward-looking statements reflecting management's current beliefs and expectations. Words such as "may," "will," "expect," "anticipate," "estimate," "intend" and similar expressions or their negatives (as well as other words and expressions referencing future events, conditions, or circumstances) are intended to identify forward-looking statements. No representations or warranties are offered in connection with the data or information provided herein. This presentation is intended for informational purposes only and may not be relied on in connection with the purchase or sale of any security. Any offering of our securities will be made, if at all, only upon the registration of such securities under applicable securities laws or pursuant to an exemption from such requirements.

Anti-SEMA4D Mab neutralizes SEMA4D barrier at tumor

margin and shifts the balance of tumor immunity

A. Sema4D

B. Increased infiltration of pro-inflammatory APC

C. Shift in balance of tumor

gradient

and CD8+ T cells

immunity in TME

Vessel

Tumor-specific Cytotoxic T Cells

Ig

Control

%CD3+CD8+

IFNg ELISPOT

Tumor

Anti-SEMA4D enhances T cell infiltration and reduces immunosuppressive M2 TAM in TGFβ driven, highly desmoplastic and immune excluded pancreatic cancer model

(6). A) C57b/6 mice were injected orthotopically with KP2 cells* (derived from the spontaneous KRASG12D; TP53Flox/Wt; P48-Cre autochthonous tumors from David Denardo, Washington University) and treated with αSEMA4D / MAb67, αPD1/MAb RMP1- 14, αCTLA-4 /MAbUC10-4F10 (10 mg/kg, twice weekly IP). Tumors were harvested after 2 weeks of treatment, weighed and dissociated for flow cytometric analysis of CD8+ T cells and M2 TAM.

Fixed Time Point Tumor Weights

Fixed Time Point CD8s

Fixed Time Point TAMs

0.4

p=0.16

20

40

P=0.16

weightTumor(g)

0.3

3500CD8/CD45

F4/80+MHCII/CD45

15

30

0.2

TGFb1

TGFb2

10

20

4000

250

0.1

5

10

200

Counts

0.0

0

Counts

150

3000

100

2500

50

Vehicle

ICB + Vehicle

anti-SEMA4D + Vehicle

anti-SEMA4D + ICB

2000

CTRL

SEMA

CTLA

COMBO

0

CTRL

SEMA

CTLA

COMBO

-1.05X

1.17X*

1.15X

1.18X

1.22X

1.09X

p=0.432

p=0.014

p=0.181

p=0.301

p=0.178

p=0.51

Counts

Pepinemab facilitates T cell infiltration into

immune excluded MSS metastatic CRC

No treatment

Pepinemab

1000

Normal

800

liver

600

400

Tumor

200

Bed

0

Resectable PDAC

Resectable melanoma

Resectable HNSCC

(n=16)

CRC resectable liver

(n=36)

(n=36)

Currently enrolled:12

Currently enrolled: 10

mets (n=16)

Currently enrolled: 5

CRC, 1 PDAC

No treatment (SOC)

No Treatment (SOC)

No treatment (SOC)

VX15/2503 (15 mg/kg)

VX15/2503 (20 mg/kg)

VX15/2503 (20 mg/kg)

VX15/2503 (20 mg/kg)

VX15/2503 (15 mg/kg)

Ipilimumab (1 mg/kg)

Ipilimumab (3 mg/kg)

VX15/2503 (20 mg/kg)

VX15/2503 (20 mg/kg)

SEMA4D

CD11c

F4/80

CD8

67

MAb

M2-TAM

MDSC

αSEMA4D

Tumor

SEMA4D is strongly expressed at the invasive margin of tumors. Antibody blockade of SEMA4D facilitates migration of APCs and T cells into the TME. (A) SEMA4D expression at invasive tumor margin restricts infiltration of PLXNB1+ DC into TME. Brackets indicate area of SEMA4D gradient. (B) Anti-SEMA4DMAb treatment promotes infiltration of pro-inflammatory CD11c+/F4-80+antigen presenting cells, while reducing CD206+ M2 macrophage and MDSC. Pro-inflammatoryAPC recruit and activate CD8+ T cells within TME. Colon26 tumor-bearingmice were treated with Control Ig or anti-SEMA4D/MAb67antibodies (50 mg/kg, weekly IP). Tumors were harvested on day 27 and FFPE sections were stained by IHC or (C) tumors were dissociated and assessed for immune cell markers by flow cytometry. Leukocytes were enriched from whole tumor digests using lympholyte-Mand cultured for 2-daysand supernatants were assessed for T cell activity by ELISPOT, n=8-12mice/group.

TGFbRI

TGFbRII

Anti-SEMA4D enhances expression of TGFbRII. Upregulation of TGF receptor

5000

8000

*

*

may result from down-regulation of its ligand, or upregulation of an independent

immune resistance mechanism. Upregulation of TGFbRII4000

is associated with APC-

6000

independent and fibroblast-dependent resistance to3000immune checkpoint therapy

Counts

and EMT has

4000

2000

(7). Potential interaction of SEMA4D/PLXN and TGFCounts β pathways

1000

2000

been reported (8,9); further investigation in ongoing.

Colon26 tumor bearing mice were treated as above. 0Tumors were harvested on

0

CTRL SEMA

CTLA

COMBO

CTRL

SEMA

CTLA

COMBO

day15 and RNA expression was analyzed using Nanostring.

-1.16X

-1.03X

-1.1X

1.33X

1.18X

1.54X

p=0.482

p=0.879

p=0.575

p=0.016

p=0.261

p=0.036

Overcoming Immune Exclusion in TME can

enhance immune checkpoint therapy by

Reduction and polarization of suppressive

myeloid cells

Reduction of fibroblast-specificTGF-β

TGFb blockade

signaling (9)

MDSC (S100A9+CD33+)

CD8+ T cells

Tumors (Cytokeratin+)

CD8 Density in Tumor Bed

M-MDSC Density in Tumor Bed

25

30

Bed

20

cells

Bed

llsCeCD8+# mmper

+CD33+S100A9#

mmper

20

orTum

15

rTumo

2

10

2

10

5

0

0

no treatment pepinemab

No treatment

pepinemab

VX15/2503 (20 mg/kg)

Nivolumab (480 mg)

Ipilimumab (1 mg/kg)

Nivolumab (480 mg)

Nivolumab (480 mg)

VX15/2503 (15 mg/kg)

VX15/2503 (20 mg/kg)

Nivolumab (3 mg/kg)

Ipilimumab (1 mg/kg)

Nivolumab (480 mg)

Ipilimumab (1 mg/kg)

2 Doses

1 Dose

1 Dose

Pre-treatment

Surgical

Biopsy

Resection

Biomarker Analysis:

EVALUATE

Safety:

Compare relative to baseline biopsy and

among Rx cohorts

PK/PD

immune profile in tumor and peripheral blood

* Total enrolled, as of NOV 1, 2019.

D.

MDSC Recruitment

E. MDSC Function

MDSC recruitment and suppressive function is

CXCL1

CXCL2

CXCL5

reversed by SEMA4D antibody blockade. (D)

Anti-SEMA4D facilitates infiltration of

T cells and pro-inflammatory APC into TME

CRC patients received neoadjuvant chemotherapy

before immunotherapy and surgery

The key observations relate to distribution of T cells and MDSC in MSS metastatic CRC. Surgical resections were analyzed from one CRC

In vitro tumor

CTRL αS4D CTRL αS4D CTRL αS4D

MOC1 HNSCC cells in vitro were exposed to Sema4D mAb (10 µg/mL) or isotype for 24 hours and analyzed for myeloid chemokine expression by qRT-PCR (in vitro tumor). Mice bearing MOC1 tumors were treated in vivo with isotype control or anti-Sema4D Ab (αS4D) (n=5/group). Whole tumor digests were analyzed for myeloid chemokine expression via qRT-PCR (whole tumor). (E) MDSC were isolated from HNSCC MOC1 in vivo tumors and co- cultured ex vivo with rSEMA4D (10 μg/ml) or antibodies, in presence of naïve T cells labeled with CFSE in a T cell suppression assay.

and reverses recruitment and activity of

MDSC and M2 TAM.

TGFβ represents

an independent

fibroblast-driven mechanism of immune

exclusion and resistance to immune

checkpoint therapy.

Anti-SEMA4D can enhance activity of both

immune checkpoint and TGFβ blockade.

Targeting multiple

pathways may

Adapted from:

overcome immune exclusion and promote

Evans EE, Paris M, Smith ES & Zauderer M. 2015, OncoImmunology

anti-tumor immunity.

patient following 3-5 weeks of treatment with pepinemab and one patient who did not receive antibody treatment. 5 micron FFPE sections were stained sequentially for each marker and scanned at 40X. Scans were co-registered for each stain in multiplex. A) ) CD8+ T cells (red) overlays on cytokeratin stain (green) at tumor/normal liver margin are shown (3.3x). 10x images from center of tumor are shown below with S100A9+/CD33+ MDSC (blue) overlays on cytokeratin stain (green) are shown. B) Total number of CD8 or MDSC cells were quantified from entire tumor bed area, normalized by area of tumor bed using Visiopharm software, and 2 sections/patient were averaged in bar graphs.

Analysis of additional patient samples is ongoing.

REFERENCES:

5.

Fisher et al, 2016. MAbs. 8(1): 150-162.

1.Clavijo PE et al. Cancer Immunol Res. 2019 ;7(2):282-291

6.

Jiang H, DeNardo et al. Gut. 2019

2.Evans, EE et al 2015. Cancer Immunol Res. 3(6):689-701.

7.

Ganesh K and Massague J. Immunity 48:626-628. 2018

3.Evans EE, Paris M, Smith ES & Zauderer M. 2015: OncoImmunology

8.

Chen Y. Cell Mol Biol Lett. 2018;23.

4.Patnaik A et al. Clin Cancer Res. 2016;22(4):827-36.

9.

Zhang C. Cancer Lett. 2019 Jul 2

CTRL αS4D CTRL αS4D CTRL αS4D

Disclaimer

Vaccinex Inc. published this content on 09 November 2019 and is solely responsible for the information contained therein. Distributed by Public, unedited and unaltered, on 09 November 2019 13:14:05 UTC

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