Abstract 3582
Background
Resistance to immune checkpoint inhibitors (ICIs) is a major unmet medical need. The TGF-beta pathway is a key immunosuppressive mechanism that correlates with resistance to PD-1/PD-L1 inhibitors. TGF-beta acts by inhibiting the recruitment and activation of anti-tumor T-cells, either directly, or indirectly through its action on cancer-associated fibroblasts. AVID200 is a receptor ectodomain trap that was rationally-designed to inhibit with pM potency TGF-beta1 and -beta3, the principal oncogenic TGF-beta isoforms. Targeting these two isoforms with AVID200 has the potential to increase the number of patients that benefit from ICIs.
Methods
The percent of patients exhibiting tumor over-expression (>30FPKM) of TGF-beta isoforms was analyzed in > 10,000 samples from the CGA RNAseq data. The potency and selectivity of AVID200 and other clinical stage TGF-beta inhibitors was assessed using an A549 cell-based. The ability of AVID200 to enhance the tumor-cell killing activity of T-cells was evaluated in vivo in a syngeneic 4T1 cancer model. The ability of AVID200 to enhance T-cell infiltration and the efficacy of ICIs was assessed in EMT-6 and MC-38 cancer models.
Results
Gene expression analysis revealed that TGF-beta1 is the predominant isoform expressed in solid tumors, with TGF-beta3 also being expressed in multiple tumor types. This indicates that it is important to target both ligand isoforms for maximal efficacy, particularly because TGF-beta 1 and 3 can functionally substitute for each other. In vitro, AVID200 exhibited the best potency (low pM) and selectivity for TGF-beta 1 & 3 vs TGF-beta 2 amongst the TGF-beta inhibitors tested. Having minimal activity on TGF-beta2 is desirable because TGF-beta2 is involved in cardiac homeostasis and the positive regulation of hematopoiesis. In vivo, AVID200 was shown to promote T-cell infiltration and to increase the anti-tumor activity of ICIs.
Conclusions
In conclusion, AVID200 efficiently neutralizes TGF-beta 1 and 3, the main oncogenic isoforms, with best-in-class potency and sensitizes tumors to immune checkpoint blockade. The AVID200 Phase 1 study in patients with solid tumors is ongoing.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Forbius (Formation Biologics).
Funding
Forbius (Formation Biologics).
Disclosure
T. Gruosso: Full / Part-time employment: Forbius (Formation Biologics). M. O’Connor: Leadership role, Licensing / Royalties, Full / Part-time employment, Officer / Board of Directors: Forbius (Formation Biologics). J. Denis: Full / Part-time employment: Forbius (Formation Biologics). R. Figueredo: Research grant / Funding (self): Forbius (Formation Biologics); Research grant / Funding (self): Trillium Therapeutics, Inc.; Research grant / Funding (self): Critical Outcome Technologies, Inc. J. Koropatnick: Licensing / Royalties: Sarissa Inc; Research grant / Funding (self): Forbius (Formation Biologics); Research grant / Funding (self): Trillium Therapeutics, Inc; Research grant / Funding (self): Critical Outcome Technologies, Inc. G. Tremblay: Licensing / Royalties: Alethia Biotherapeutics; Full / Part-time employment: Forbius (Formation Biologics). I.A. Tikhomirov: Leadership role, Shareholder / Stockholder / Stock options, Licensing / Royalties, Full / Part-time employment, Officer / Board of Directors: Forbius (Formation Biologics).
Resources from the same session
3309 - Heat Shock Protein 90 chaperones and Protein Kinase D3 regulates androgen-independent prostate cancer development
Presenter: Attila Varga
Session: Poster Display session 1
Resources:
Abstract
3441 - The SWI/SNF driven reprograming for the AR cistrome is NSD2 dependent
Presenter: Katia Ruggero
Session: Poster Display session 1
Resources:
Abstract
1659 - IGF1R inhibition affects the survival of HT29 cancer cells by alterations of the TLR9- and autophagy signaling
Presenter: Györgyi Műzes
Session: Poster Display session 1
Resources:
Abstract
1379 - Characterization of atypical dMMR (deficient MisMatch Repair) tumors: a study from a large cohort of 4948 cases
Presenter: Marion Jaffrelot
Session: Poster Display session 1
Resources:
Abstract
1657 - Modulation of TLR9-dependent autophagy response via inhibition of c-Met signaling influences the survival of HT29 cancer cells
Presenter: Ferenc Sipos
Session: Poster Display session 1
Resources:
Abstract
3045 - Positive Feedback Activation of Notch Signal by Obesity Enhances Colorectal Tumorigenicity
Presenter: Dake Chu
Session: Poster Display session 1
Resources:
Abstract
2285 - The Pathological and Functional Roles of BRPF1 in Hepatocellular Carcinoma
Presenter: Lai Hung Carol Cheng
Session: Poster Display session 1
Resources:
Abstract
3210 - Protein tyrosine phosphatase non-receptor type 3 (PTPN3) could be a new therapeutic target for pancreatic cancer.
Presenter: Akio Yamasaki
Session: Poster Display session 1
Resources:
Abstract
3920 - A Novel bispecific BCMAxCD3 T cell engaging antibody that treat multiple myeloma (MM) with minimal cytokine serection
Presenter: Zhenyu Li
Session: Poster Display session 1
Resources:
Abstract
2691 - Quantitative spatial profiling of lymphocyte-activation gene 3 (LAG-3)/major histocompatibility complex class II (MHC II) interaction in gastric and urothelial tumors
Presenter: Cyrus Hedvat
Session: Poster Display session 1
Resources:
Abstract