Abstract 2661
Background
Tumor stroma represents 20-60% of solid tumor mass and plays a key role in promotion, invasiveness and metastasis. FAP-expressing CAFs, the predominant stroma cell type, are involved in tumor immune response. A novel antibody-drug conjugate, OMTX705, was generated through CYS-based conjugation of a new anti-FAP humanized antibody to a novel cytolysin using an optimized vcPABA linker.
Methods
In vivo studies were performed in patient-derived xenograft models for NSCL cancer in humanized mice. Tumor volume and animal weight were monitored over 4-week treatment with OMTX705 administered intravenously at different doses, alone or combined with Pembrolizumab. FACS and IHC analysis of markers for immune cells, CAFs, and cell proliferation or apoptosis, were performed on tumor samples to study OMTX705 effect on tumor stroma and elucidate its mechanism of action. In vitro assays were performed to support in vivo data. OMTX705 stability in blood was determined after i.v administration in CD1 mice.
Results
OMTX705 showed 100% tumor growth inhibition and higher activity than Pembrolizumab in the humanized PDX model for NSCL cancer without weight loss. Full tumor regression was found in 10% of mice treated with OMTX705 alone and 20% in combination with Pembrolizumab. A significant delay in tumor recurrence was observed. OMTX705 was 100% stable in bloodstream after 7 days. FACS analysis evidenced a significant increase in CD8(+) T cell tumor infiltration. Results from in vitro studies and IHC analysis of tumors identified CAFs as highly specific reservoir cells for OMTX705 from which the high potent cytolysin payload is released to induce apoptosis of adjacent tumor cells and CD8(+) T cell immunomodulation.
Conclusions
OMTX705 alone induces tumor shrinkage, and full regression with Pembrolizumab, through highly specific, CAF-dependent and long-lasting modulation of tumor stroma. This novel mechanism of action makes OMTX705 a potent and innovative strategy for NSCL cancer treatment. Considering FAP is expressed in a wide array of carcinomas, OMTX705 represents a highly promising and well-tolerated candidate to treat solid tumors with low response to anti-PD1 immunotherapies.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Oncomatryx Biopharma, S.L.
Funding
Oncomatryx Biopharma, S.L.
Disclosure
M. Fabre: Full / Part-time employment: Oncomatryx Biopharma, S.L. C. Ferrer: Full / Part-time employment: Oncomatryx Biopharma, S.L. S. Domínguez-Hormaetxe: Full / Part-time employment: Oncomatryx Biopharma, S.L. R. Kontermann: Advisory / Consultancy: Oncomatryx Biopharma, S.L.; Advisory / Consultancy: SunRock Biopharma, S.L.; Advisory / Consultancy: Roche. K. Pfizenmaier: Advisory / Consultancy: Oncomatryx Biopharma, S.L.; Advisory / Consultancy: SunRock Biopharma, S.L. O. Seifer: Research grant / Funding (institution): Oncomatryx Biopharma, S.L. M.D. Vivanco: Research grant / Funding (institution): Oncomatryx Biopharma, S.L. S. Lee: Research grant / Funding (institution): Oncomatryx Biopharma, S.L. P. López-Casas: Full / Part-time employment: Bioncotech Therapeutics, S.L. M. Abbas: Full / Part-time employment: Tube Pharmaceuticals GmBH. W. Richter: Advisory / Consultancy: Oncomatryx Biopharma, S.L.; Shareholder / Stockholder / Stock options, Full / Part-time employment: Tube Pharmaceuticals GmBH. L. Simon: Honoraria (self), Leadership role, Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Licensing / Royalties, Full / Part-time employment, Patents: Oncomatryx Biopharma, S.L.; Honoraria (self), Leadership role, Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Licensing / Royalties, Full / Part-time employment, Patents: Patia Biopharma, SA de CV; Honoraria (self), Leadership role, Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: Patia Europe, S.L.; Shareholder / Stockholder / Stock options, Full / Part-time employment: PatiaCan, SA de CV; Honoraria (self), Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Permedika Entrepeneurs; Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options: SunRock Biopharma, S.L.; Licensing / Royalties, Patents: Quimatryx, S.L.; Shareholder / Stockholder / Stock options: Stemcell Therapeutics, S.L.; Shareholder / Stockholder / Stock options: Helenes Ventures, S.L.; Shareholder / Stockholder / Stock options: Nellum Corp. M. Hidalgo: Advisory / Consultancy: Oncomatryx Biopharma, S.L.; Honoraria (self), Advisory / Consultancy, Shareholder / Stockholder / Stock options: Champions Oncology; Honoraria (self), Advisory / Consultancy, Shareholder / Stockholder / Stock options: Pharmacite Biotech; Shareholder / Stockholder / Stock options: BioOncotech; Shareholder / Stockholder / Stock options: Nelum; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Pfizer; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self): MSD Oncology; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Celgene; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: BiolineRX; Honoraria (self), Advisory / Consultancy: Roche/Genentech; Honoraria (self), Advisory / Consultancy: SOBI; Honoraria (self), Advisory / Consultancy: Agenus; Honoraria (self), Advisory / Consultancy: Erytech Pharma; Advisory / Consultancy: Merck; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca/MedImmune; Advisory / Consultancy, Travel / Accommodation / Expenses: Menarini; Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Research grant / Funding (self): Bicycle Therapeutics; Research grant / Funding (self): Asana Biosciences.
Resources from the same session
3664 - Longitudinal changes in cell-free DNA (cfDNA) methylation levels identify early non-responders to treatment in advanced solid tumors
Presenter: Andrew Davis
Session: Poster Display session 3
Resources:
Abstract
3212 - Multigene panel testing results for hereditary breast cancer in 1325 individuals: implications for gene selection and considerations for guidelines.
Presenter: Georgios Tsaousis
Session: Poster Display session 3
Resources:
Abstract
2591 - PIK3R5 genetic predictors of hypertension induced by VEGF-pathway inhibitors
Presenter: Julia Quintanilha
Session: Poster Display session 3
Resources:
Abstract
4377 - ERBB2 mRNA as a predictor in HER2-positive (HER2+)/hormone receptor-positive (HR+) metastatic breast cancer (BC) treated with HER2 blockade in combination with endocrine therapy (ET): a retrospective analysis of the ALTERNATIVE and SOLTI-PAMELA trials.
Presenter: Nuria Chic
Session: Poster Display session 3
Resources:
Abstract
3439 - Early on-treatment vs pre-treatment tumor transcriptomes as predictors of response to neoadjuvant therapy for HER2-positive inflammatory breast cancer
Presenter: Sonia Pernas
Session: Poster Display session 3
Resources:
Abstract
2512 - AXL expression predicts poor prognosis and lack of efficacy of anti-angiogenic and anti-epidermal growth factor receptor (EGFR) agents in patients (pts) with RAS wild type (WT) metastatic colorectal cancer (mCRC)
Presenter: Claudia Cardone
Session: Poster Display session 3
Resources:
Abstract
4061 - Prevalence of EGFR mutations and its correlation with Egyptian patients’ human kinetics (PEEK Study)
Presenter: Adel Ibrahim
Session: Poster Display session 3
Resources:
Abstract
2547 - Evaluation of tumor microenvironment identifies immune correlates of response to combination immunotherapy with margetuximab (M) and pembrolizumab (P) in HER2+ gastroesophageal adenocarcinoma (GEA)
Presenter: Sergio Rutella
Session: Poster Display session 3
Resources:
Abstract
4671 - Clinicopathological and molecular criteria assessment for the screening of hypermutated proficient mismatch repair (pMMR) colorectal cancers (CRC) with exonucleasic domain POLE (edPOLE) mutations (mt).
Presenter: Benoit Rousseau
Session: Poster Display session 3
Resources:
Abstract
3862 - Tumor mutation burden and microsatellite instability in colorectal cancer
Presenter: Francesca Fenizia
Session: Poster Display session 3
Resources:
Abstract