On November 12, 2021 Kymera Therapeutics, Inc. (NASDAQ: KYMR), a clinical-stage biopharmaceutical company advancing targeted protein degradation (TPD) to deliver novel small molecule protein degrader medicines, reported that new preclinical data from its STAT3 degrader program at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)’s (SITC) (Free SITC Whitepaper) 36th Annual Meeting, taking place from November 10 – 14, 2021 in Washington, D.C. and virtually (Press release, Kymera Therapeutics, NOV 12, 2021, View Source [SID1234596080]).
Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:
Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing
Schedule Your 30 min Free Demo!
The results reveal Kymera’s potent and selective STAT3 degraders exhibited anti-tumor activity in multiple preclinical animal models of solid and hematologic malignancies that respond poorly to immunotherapies. Administration of a tool STAT3 degrader, KTX-201, led to molecular and cellular changes in the tumor microenvironment that were predictive of favorable responses to checkpoint inhibition. Consistent with these findings, KTX-201 sensitized these tumors to anti-PD1 treatment when administered in combination, leading to durable anti-tumor responses and development of long-term immunological memory.
"These encouraging findings underscore the potential power of targeted protein degradation (TPD) to address a range of cancers driven by STAT3, an undruggable transcription factor with effects on both tumor cells and the tumor microenvironment," said Jared Gollob, MD, Chief Medical Officer at Kymera Therapeutics. "We believe our novel data offer critical insights into the antitumor activity of Kymera’s STAT3 degraders, particularly their potential to synergize with immunotherapies such as checkpoint blockade – which only work in a small percentage of patients – thereby providing a rationale for selectively degrading STAT3 to sensitize cancers to immune checkpoint inhibition in the clinic."
STAT3 is a transcription factor activated through a variety of different cytokine and growth factor receptors via Janus kinases (JAKs), as well as through oncogenic fusion proteins and mutations in STAT3 itself. Long considered an "undruggable" target, STAT3 hyperactivation is prominent in numerous liquid and solid tumors, including clinically aggressive lymphomas. Kymera is developing selective STAT3 degraders for the treatment of hematological malignancies and solid tumors, as well as autoimmune diseases and fibrosis. Kymera’s STAT3 degraders have previously demonstrated strong anti-tumor effects in mouse xenograft and syngeneic models of liquid and solid cancers.
"Research presented to date on Kymera’s STAT3 degraders has bolstered our knowledge of the mechanisms underlying the anti-tumor and immunomodulatory effects associated with STAT3 degradation," said Nello Mainolfi, PhD, Co-Founder, President and CEO, Kymera Therapeutics. "We are eager to advance KT-333, a first-in-class selective STAT3 degrader for liquid and solid tumors into Phase 1 clinical trials by the end of 2021."
Additional Research Highlights:
Treatment of CT-26 (colorectal cancer) and A20 (B-cell lymphoma) tumor-bearing mice with a STAT3 degrader resulted in significant tumor growth inhibition compared to controls, with loss of STAT3 protein in both tumor cells and TME.
Treatment of CT-26 and A20 tumor-bearing mice with a STAT3 degrader led to a decrease in M2 polarized macrophages and concomitant increases in M1 polarized macrophages and tumor infiltrating lymphocytes.
Gene expression profiling of STAT3 degrader-treated CT-26 tumors showed marked increases in proinflammatory genes including T cell and M1 macrophage activation markers, compared to controls.
Induction of an Ifnγ-responsive gene signature (Ifnγ, Stat1, Cxcl9, Cxcl10, Ido1) in CT-26 tumors showed that STAT3 degradation results in a T cell inflamed phenotype associated with responsiveness to immune checkpoint therapy.
On-treatment tumors showed an upregulation of genes such as Pdl1, Ctla4, Lag3 which reflect T cell activation as well as counterregulatory mechanisms.
STAT3 degradation in combination with anti-PD1 resulted in robust synergy in the CT-26 model with 60% complete responses and development of immunological memory as confirmed by tumor rechallenge studies.
Studies are underway to ascertain the applicability of this combination therapy in different tumor immune contextures, and to elucidate the mechanistic basis of synergy.
Presentation at SITC (Free SITC Whitepaper) Annual Meeting:
Title: Targeted STAT3 Degradation Leads to Remodeling of an Immunosuppressive Tumor Microenvironment and Subsequent Sensitization to Immune Checkpoint Therapy
Abstract Number: 603
Session Time: 7:00 a.m. – 8:30 a.m. ET on Friday, Nov. 12, 2021
Location: Poster Hall (Hall E), Walter E. Washington Convention Center, Washington, D.C.
Presenter: Joyoti Dey, Associate Director, Translational Medicine, Kymera Therapeutics