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
4021 - Prospective pathological experience with research biopsies in the context of clinical trials at Vall d’Hebron Institute of Oncology
Presenter: Paolo Nuciforo
Session: Poster Display session 3
Resources:
Abstract
5603 - Development of a comprehensive next-generation targeted sequencing assay for detection of gene-fusions in solid tumors
Presenter: Vinay Mittal
Session: Poster Display session 3
Resources:
Abstract
4952 - Next-generation sequencing for better treatment strategy of cancer of unknown primary (CUP)
Presenter: Kang Kook Lee
Session: Poster Display session 3
Resources:
Abstract
4590 - Circulating-free DNA analysis from long-term surviving metastatic colorectal cancer patients undergoing surgery for resectable disease.
Presenter: Michele Ghidini
Session: Poster Display session 3
Resources:
Abstract
3696 - Ultra-sensitive detection of circulating tumor DNA identifies patients in high risk of recurrence in early stages melanoma
Presenter: Filip Janku
Session: Poster Display session 3
Resources:
Abstract
4295 - Identification of the founder BRCA1 mutation c.4117G>T (p.Glu1373*) recurring in Abruzzo and Lazio regions of Central Italy and predisposing to breast/ovarian and BRCA1-related cancers
Presenter: Daniela Di Giacomo
Session: Poster Display session 3
Resources:
Abstract
2214 - Enzalutamide (ENZA) and Apalutamide (APA) In vitro chemical reactivity studies and Activity in a Mouse Drug Allergy Model (MDAM)
Presenter: Mausumee Guha
Session: Poster Display session 3
Resources:
Abstract
5044 - Influence of genetic variation in COMT on cisplatin-induced nephrotoxicity in cancer patients.
Presenter: Bram Agema
Session: Poster Display session 3
Resources:
Abstract
3293 - Cardioprotective and anti-inflammatory effects of Empagliflozin during treatment with Doxorubicin: a cellular and preclinical study
Presenter: Vincenzo Quagliariello
Session: Poster Display session 3
Resources:
Abstract
3324 - Breast Cancer Organoids Model Treatment Response of HER2 Targeted Therapy in HER2-mutant Breast Cancer
Presenter: Xuelu Li
Session: Poster Display session 3
Resources:
Abstract