From 29 March – April 03, VHIO faculty joined fellow cancer researchers, physician-scientists, population investigators, and other oncology professionals as well as cancer survivors, patients, and advocates from across the globe to attend the 110th Annual Meeting of the American Association for Cancer Research (AACR) in Atlanta (GA, USA). Themed, Integrative Cancer Science. Global Impact. Individualized Patient Care., AACR 2019 continued to build on the successes of its meetings past by delivering the very latest insights spanning the full breadth and depth of cancer science and medicine – including translational, clinical and prevention research.
Just some of the many VHIO contributions to this year’s scientific program included Rodrigo Dienstmann, Principal Investigator of the VHIO Oncology Data Science (ODysSey) Group, who was invited as a speaker to present on the Targeted Immunotherapeutics Interactome: Small Molecules and Antibody-drug Conjugates (www.aacr.org/interactome), a tool that applies text mining to the AACR Annual Meeting Abstracts to create a visual map of the publications on antibody-drug conjugates and small molecule immunotherapeutics.
This Special Session, co-chaired by Rodrigo and Justin Guinney, Sage Bionetworks (Seattle, WA, USA), updated on the most relevant networks of abstracts and discussed how the field has evolved over recent years. Commenting for VHIO Communications Rodrigo said, “We presented the most promising drugs and targets and showed how publications by academic groups and the pharmaceutical industry are interrelated. Invited experts on the clinical development of these agents, Anthony W. Tolcher from NEXT Oncology in San Antonio, Texas, and Stéphane Champiat, Institute Gustave Roussy, Villejuif, France, explored the current challenges and opportunities, and in so doing, also signposted possible new directions.”
Preliminary data from a phase I study of MSC-1, a humanized anti-LIF monoclonal antibody, in patients with advanced solid tumors were presented. This humanized LIF neutralizing antibody was developed by Co-Director of VHIO’s Preclinical and Translational Program, and ICREA Professor, Joan Seoane, in close collaboration with VHIO-born spin-off company, Mosaic Biomedicals S.L. The study, coordinated by VHIO’s Director, Josep Tabernero, and co-first authored by Alison Schram and David M. Hyman, Memorial Sloan Kettering Cancer Center (MSKCC, New York, USA), also counted on the expertise of VHIO co-collaborators, Elena Garralda, Director of our Research Unit for Molecular Therapy of Cancer (UITM) “la Caixa” and Principal Investigator of our Early Clinical Drug Development Group, and Irene Braña, Phase I Investigator of her group.
Leukemia inhibitory factor (LIF) is involved in many physiological and pathological processes and is highly expressed across multiple tumor types, correlating with a poor prognosis. “We believe that LIF contributes to tumour growth and progression by acting on several aspects of cancer biology, including immunosuppression of the tumour microenvironment and regulation of cancer-initiating cells. For this very reason we developed MSC-1, the first monoclonal antibody that powerfully and selectively inhibits LIF,” explained Joan after the session.
As previously shown in mouse models, blocking LIF with MSC-1 reduces tumor growth and leads to the reprogramming of the tumor microenvironment through the differentiation of immunosuppressive macrophages and the modulation of different types of immune cells. These findings formed the pillars supporting the hypothesis that therapy with MSC-1 could result in promising clinical activity.
For this new study, patients with advanced, relapsed or refractory solid tumors were enrolled and were treated with MSC-1 intravenously once every three weeks. Initial results show that this novel anti-cancer therapy is safe and no treatment-limiting toxicity was reported. Further studies will seek to confirm anti-cancer activity across various tumor types in expansion cohorts.
This year’s program also covered some of the most promising and hot new directions in cancer treatment and care including immune-oncology. Ignacio Matos, Phase I Investigator of VHIO’s Early Clinical Drug Development Group and our UITM – “la Caixa,” headed by Elena Garralda, contributed to two studies against microcytic lung cancer. Led by Hyun Cheol Chung, Yonsei Cancer Center (Seoul, South Korea), this research focused on the development of pembrolizumab, an anti-PD-1 monoclonal antibody.
Results from two clinical studies testing the efficacy and safety of this antibody in patients with advanced small cell lung cancer (SCLC) after two or more lines of prior therapy were presented together. “In the first, patients had PD-L1 positive tumors, while in the second, this was not a requirement. The primary endpoint in both studies was objective response rate, and the drug demonstrated promising antitumor activity,” explained Ignacio.
Duration of response, progression-free survival (PFS) and overall survival (OS) were secondary endpoints in both studies, with pembrolizumab showing significant results. Two of the patients had a complete response and another 14 had a partial response. In the majority of these 16 patients the duration of the response was longer than 12 months.
Ignacio Matos also participated in another phase I study, led by Funda Meric-Bernstam, MD Anderson Cancer Cancer Center (Houston, TX, USA), whose results were also presented during the meeting. This trial sought to verify the activity of TAS-120, an oral FGFR1-4 tyrosine kinase inhibitor. This protein is responsible for the regulation of cell growth and division, which helps in the determination of cell type and is key in the formation of blood vessels as well as embryonic development.
“The study has established the maximum safe dose of this inhibitor. Continuous oral dosing of TAS-120 of up to 20 mg were safe and showed preliminary anti-tumour activity in selected patients with different tumor types and alterations of FGF/FGFR,” summarized Ignacio. This clinical trial included patients with primary tumors of the central nervous system, urothelial carcinoma, breast cancer, colorectal cancer and gastro-oesophageal cancer.
Another study first-authored by David M. Hyman, Memorial Sloan Kettering Cancer Center (MSKCC, New York, USA) assessed the safety of LOXO-195, a selective next-generation tropomyosin receptor kinases (TRK) inhibitor. TRK fusion events are rare but recurrent and have been identified across diverse pediatric and adult cancers. The first TRK inhibitor to be approved by the Food and Drug Administration (FDA) was larotrectinib.
The results from this multi-center study that also counted on the participation of VHIO’s Elena Garralda, showed that LOXO-195 is well tolerated in doses of up to 100 mg twice daily, although additional studies are warranted to establish both the optimal dose and daily schedule. Talking to VHIO Communications, Elena noted, “While this study has shown preliminary efficacy in TRK fusion-positive patients with acquired TRK kinase domain resistance mutations, additional data are needed to define activity in each specific kinase mutation. These findings might however open up a new therapeutic avenue for patients with TRK fusion cancer who progress on first-generation TRK inhibitors.”
Several other VHIO researchers also participated at AACR 2019 including Violeta Serra, Principal Investigator of our Experimental Therapeutics Group; Judith Balmaña, Head of VHIO’s Hereditary Cancer Genetics Group; and Cristina Saura, who directs our Breast Cancer & Melanoma Group. They jointly led a study on reversal of PARP inhibitor resistance through response to replicative stress. In collaboration with Joaquín Arribas, Co-Director of Preclinical and Translational Research at VHIO, they also co-authored a study on biomarkers of response to WEE1 and ATR inhibitors against triple negative breast cancer.
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