On November 12, 2021 Bolt Biotherapeutics, Inc. (Nasdaq: BOLT), a clinical-stage biotechnology company pioneering a new class of immuno-oncology agents that combine the targeting precision of antibodies with the power of both the innate and adaptive immune systems, reported the company will be presenting posters with new data from three of its pipeline programs on Saturday, Nov. 13, at the 2021 Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting, being held virtually and in person in Washington, D.C. from Nov. 10-14 (Press release, Bolt Biotherapeutics, NOV 12, 2021, View Source [SID1234618693]). Each presentation highlights the progress made in preclinical studies to demonstrate the potential for each pipeline candidate as a novel approach for the treatment for cancer.

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!

"We are presenting new data for three of our pipeline programs that demonstrate the depth of our technology platform and the expertise of our team in modulating myeloid cell biology to develop promising therapeutic candidates," said David Dornan, Ph.D., Bolt Biotherapeutics’ Chief Scientific Officer. "Repolarizing tumor-associated macrophages, or TAMs, to become tumor destructive via the novel target Dectin-2 is groundbreaking work that may be synergistic with our entire Boltbody ISAC portfolio. Our work targeting CEA and PD-L1 reinforces our commitment to develop therapeutics that could have promising activity against solid tumors where limited treatment options are available."

Highlights of the three poster presentations follow, and copies of the posters are available on the Bolt Biotherapeutics website.
Poster #784: "BDC-2034: Discovery of a CEA-targeting Immune-Stimulating Antibody Conjugate (ISAC) for Solid Tumors"
Presenter: William G. Mallet, Ph.D.
Details: Saturday, Nov. 13, 2021, 7:00 a.m. – 8:30 p.m. EST, Poster Hall

Key findings from the study:
CEA is a well-validated tumor antigen for the development of targeted therapies addressing multiple types of solid tumors, such as colon cancer, where new treatment options are urgently needed. Given the abundance of innate immune cells in CEA-expressing cancers, innate immune stimulation presents a promising therapeutic strategy. Applying Boltbody platform technology, Bolt Biotherapeutics scientists have developed a novel CEA-targeted ISAC, BDC-2034, to exploit over-expression of CEA in cancers. BDC-2034 is designed to trigger the innate immune system, leading to adaptive anti-tumor immunity and tumor destruction.

BDC-2034 comprises a novel CEA-targeted, pro-phagocytic antibody conjugated to a proprietary TLR7/8 agonist payload. Both elements of this molecule are finetuned for selective immune activation in tumors.
New data reported at SITC (Free SITC Whitepaper) 2021 demonstrate both tumor cell clearance and innate immune activation in cellular and in vivo models of CEA-expressing cancers. Further, systemic administration in tumor-bearing animals results in tumor-selective immunity.
Based on these data, Bolt Biotherapeutics designated BDC-2034 as a clinical candidate and is currently conducting IND-enabling studies with the expectation to initiate BDC-2034 clinical development in 2022.
Poster #782: "PD-L1-targeted ISAC combines myeloid cell activation, immune-checkpoint inhibition and ADCP to improve anti-tumor efficacy over anti-PD-L1 antibodies in preclinical models"
Presenter: Marcin Kowanetz, Ph.D.
Details: Saturday, Nov. 13, 2021, 7:00 a.m. – 8:30 p.m. EST, Poster Hall

Key findings from the study:
Bolt Biotherapeutics scientists are presenting for the first time preclinical data on a novel multifunctional PD-L1-targeted Boltbody ISAC that has demonstrated the potential to improve upon the efficacy of PD-L1/PD-1 inhibition, especially in tumor types that do not respond well to immune-checkpoint inhibition.

Bolt Biotherapeutics’ PD-L1 ISAC uniquely combines three mechanisms of action: the ADCP and myeloid cell activation of an ISAC, plus immune-checkpoint inhibition with the ability to act through PD-L1 expressed on both tumor and immune cells.
Data presented at SITC (Free SITC Whitepaper) 2021 demonstrate how PD-L1 ISAC induces robust, target-dependent activation of the immune system, including induction of immunological memory.
Treatment with PD-L1 ISACs led to an effective anti-tumor response that was substantially improved over PD-L1 antibody blockage in preclinical models.
Poster #862: "Dectin-2, a novel target for tumor macrophage reprogramming in cancer immunotherapy"
Presenter: Justin A. Kenkel, Ph.D.
Details: Saturday, Nov. 13, 2021, 7:00 a.m. – 8:30 p.m. EST, Poster Hall

Key findings from the study:
For the first time, Bolt Biotherapeutics is presenting data providing preclinical validation of Dectin-2, formerly referred to as TAM1, as a novel target for cancer immunotherapy. Expressed by tumor-associated macrophages (TAMs), Dectin-2 is a pattern recognition receptor that stimulates proinflammatory cytokine production and antigen presentation to drive innate and adaptive immune responses.

Findings reported at SITC (Free SITC Whitepaper) 2021 demonstrate that agonism of Dectin-2 on TAMs elicits secretion of pro-inflammatory cytokines and chemokines capable of invoking productive anti-tumor immunity.
In murine tumor models, Dectin-2 agonism mediates anti-tumor efficacy in a CD8 T cell-dependent manner and induces immunological memory against the tumor.
Bolt Biotherapeutics scientists have generated Dectin-2 agonist antibodies that show the potential to reprogram tumor-supportive macrophages into tumor-destructive macrophages.
About the Boltbody Immune-Stimulating Antibody Conjugate (ISAC) Platform
ISACs are a new category of immunotherapy that combines the precision of antibody targeting with the strength of the innate and adaptive immune systems. Boltbody ISACs comprise three primary components: a tumor-targeting antibody, a non-cleavable linker, and a proprietary immune stimulant to activate the patient’s innate immune system. By initially targeting a single marker on the surface of a patient’s tumor cells, an ISAC can create a new immune response by activating and recruiting myeloid cells. The activated myeloid cells start a feed-forward loop by releasing cytokines and chemokines, chemical signals that attract other immune cells and lower the activation threshold for an immune response. This reprograms the tumor microenvironment and invokes an adaptive immune response that targets the tumor, with the goal of durable responses for patients with cancer.

On November 12, 2021 Cue Biopharma, Inc. (Nasdaq: CUE), a clinical-stage biopharmaceutical company engineering a novel class of injectable biologics to selectively engage and modulate targeted T cells directly within the patient’s body, reported the presentation of interim data further demonstrating the tolerability and antitumor activity potential of CUE-101 as a monotherapy as part of the Company’s ongoing clinical trial for the treatment of recurrent/metastatic HPV+ head and neck cancer in a poster at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)’s 36th Annual Meeting (SITC 2021) (Press release, Cue Biopharma, NOV 12, 2021, View Source [SID1234608267]). Early data from the CUE-101 combination study with pembrolizumab will also be discussed, supporting the potential for mechanistic activity in frontline HPV+ HNSCC patients. SITC (Free SITC Whitepaper) 2021 will be held in Washington, D.C. and virtually November 10-14.

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!

Additionally, the Company will present two posters highlighting the broad potential of the interleukin 2 (IL-2)-based CUE-100 series for treating multiple cancers. This includes representative preclinical data from CUE-102, Cue Biopharma’s next clinical candidate developed to selectively target Wilms’ Tumor 1 (WT1) cancers, and preclinical progress on the Company’s Neo-STAT and RDI-STAT (Re-Directed Immuno-STAT) platforms, which provide modularity, flexibility and scalability and address tumor heterogeneity and tumor resistance or escape mechanisms.

SITC 2021 Presentation Highlights:

Title: A phase 1 trial of CUE-101, a novel HPV16 E7-pHLA-IL2-Fc fusion protein, alone and in combination with pembrolizumab in patients with recurrent/metastatic HPV16+ head and neck cancer
Poster #: 438
Presenter: Dr. Sara I. Pai, M.D., Ph.D., associate professor, Department of Surgery; Director, Translational Research in Head and Neck Cancer Massachusetts General Hospital, Harvard Medical School, Boston MA
Date: Saturday, November 13, 2021, Poster Hall (Hall E) 7 a.m.–8:30 p.m. EST

Data as of November 2, 2021, include:

A durable partial response (PR) with an ongoing duration of 30 weeks and five durable stable disease responses (SD), as determined by RECIST 1.1. criteria, out of the 13 evaluable patients dosed at the recommended Phase 2 dose of 4mg/kg as part of the monotherapy trial.
Pharmacodynamic (PD) signals of expansion of HPV16+ cytotoxic T cells were observed in the monotherapy trial, which confirm CUE-101 mechanism of action by activation of tumor-specific T cells.
Demonstrated favorable tolerability to date, with more than 190 cumulative doses administered. Reported mild adverse events resolved while patients continued therapy.
Early signs of clinical activity of CUE-101 in combination with pembrolizumab with 3 out of 3 patients from cohort 2 at 2mg/kg, demonstrating tumor reductions in target lesions on their first scan after having received two cycles of therapy. Cohort 3 is currently enrolling.
"I am encouraged by the preliminary anti-tumor activity of CUE-101 and the positive tolerability profile, which are necessary to improve the survival and quality of care for this relatively young patient population," said Sara Pai M.D., Ph.D., associate professor of surgery and director of Translational Research in Head and Neck Cancer at the Massachusetts General Hospital, and principal investigator of the CUE-101 Phase 1 clinical trial. "Until this trial we haven’t seen an ‘off-the-shelf‘ HPV-targeted biologic administered in an outpatient setting with such durable responses in the second- and third-line treatment for recurrent/metastatic HPV16+ head and neck cancer patients and it is a significant advancement, presenting a potential path forward for a new therapeutic standard."

Ken Pienta, acting chief medical officer of Cue Biopharma, added, "We are very pleased by the emerging clinical data and growing body of evidence demonstrating the clinical potential of CUE-101 as a monotherapy in a highly pretreated, refractory, metastatic HPV+ HNSCC setting. In addition, we are encouraged by the promising, albeit early, emerging data from our combination study with pembrolizumab demonstrating potential mechanistic activity with the prospects of expanding patient reach and enhancing therapeutic responses. It is also encouraging to observe histology data demonstrating enhanced penetration of cytotoxic CD8+ T cells or "killer" T cells within the tumor and anti-tumor activity in patients failing 2-3+ previous lines of treatment."

Title: CUE-102 selectively activates and expands WT1-specific T cells for the treatment of patients with WT1+ malignancies
Poster #: 720
Presenter: Dr. Christie Zhang, Ph.D., senior scientist, discovery and translational immunology, Cue Biopharma
Date: Friday, November 12, 2021, Poster Hall (Hall E) 7 a.m.–8:30 p.m. EST

Multiple in vitro assessments demonstrated that CUE-102 selectively activated and expanded WT1-specific CD8+ T cells from peripheral blood mononuclear cells (PBMC) of healthy donors.
These CUE-102-expanded CD8+ T cells exhibited polyfunctional and cytotoxic responses upon challenge with WT1-presenting target cells.
Data showed that the attenuation of the interleukin 2 (IL-2) domains of CUE-102 led to a reduction of indiscriminate IL-2 activity, similar to results obtained with CUE-101.
In vivo studies in human leukocyte antigen (HLA)-A2 transgenic mice confirmed that CUE-102 elicited and expanded WT1-specific CD8+ T cells from naïve mice without significantly altering the frequencies of other immune lineages.
The WT1-specific CD8+ T cells expanded in vivo exhibited polyfunctionality and selectively killed WT1-presenting target cells in vivo.
Title: Targeting engineered interleukin-2 (IL-2) to antigen specific T cells via novel biologic platforms
Poster #: 793
Presenter: Raymond J. Moniz, associate director, discovery and translational immunology, Cue Biopharma
Date: Friday, November 12, 2021, Poster Hall (Hall E) 7 a.m.– 8:30 p.m. EST

Data demonstrated that the Company’s Neo-STAT (NST) biologics can be engineered with a diversity of T cell epitopes by efficient conjugation into an empty HLA-binding pocket, and that these molecules activated and expanded antigen specific T cells in vitro.
Data additionally demonstrated that the Company’s RDI-STAT biologics, were able to expand anti-viral T cell repertoires and drive anti-viral T cell redirected killing of tumor-associated antigen (TAA)-expressing cells.
In contrast to pan anti-CD3 bispecific molecules, RDI-STATs demonstrated significantly lower induction of pro-inflammatory cytokines, thus avoiding systemic activation of all T cells and offering a superior safety profile.
Anish Suri, Ph.D., president and chief scientific officer of Cue Biopharma, said, "The demonstration of CUE-102 to activate and expand WT1-specific cytotoxic CD8+ T cells in vivo further supports the modularity of our platform and enhances the potential of our CUE-100 series to address a diversity of cancers, supporting the advancement of CUE-102 into the clinic. An Investigational New Drug filing for CUE-102 is scheduled for the first quarter of 2022. In addition, the data presented on our Neo-STAT and RDI-STAT platforms continue to demonstrate the versatility and modularity of our biologics to potentially address multiple cancers with flexibility and scalability. We are highly encouraged as we continue to explore the breadth of opportunities with our Immuno-STAT, Neo-STAT and RDI-STAT biologics platforms, to develop novel therapies that address diverse patient populations, tumor heterogeneity and tumor escape mechanisms."

For more information on all three posters please visit: View Source

About the CUE-100 Series
The CUE-100 series consists of Fc-fusion biologics that incorporate peptide-major histocompatibility complex (pMHC) molecules along with rationally engineered interleukin 2 (IL-2) molecules. These singular biologics are anticipated to selectively target, activate and expand a robust repertoire of tumor-specific T cells directly in the patient’s body. The binding affinity of IL-2 for its receptor has been deliberately attenuated to achieve preferential selective activation of tumor-specific effector T cells while reducing potential for effects on regulatory T cells (Tregs) or broad systemic activation, potentially mitigating the dose-limiting toxicities associated with current IL-2-based therapies.

About the CUE-101 Clinical Trial
The trial (NCT03978689) is a multi-center, first-in-human, open-label Phase 1 dose escalation and expansion study evaluating the safety, anti-tumor effect and immunogenicity of CUE-101 as a monotherapy in second-line patients with confirmed human papilloma virus positive recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HPV+ HNSCC) and HLA-A*02:01 serotype. Patients receive CUE-101 as a monotherapy ranging from 0.06 mg/kg to 8 mg/kg. The maximum tolerated dose (MTD) has not been identified and a Phase 2 4 mg/kg dose has been selected. The company has expanded the study to evaluate CUE-101 in combination with 200 mg of KEYTRUDA (pembrolizumab) as first-line treatment in patients with HPV16-driven recurrent/metastatic HNSCC. Enrollment continues in both monotherapy and combination cohorts.

About CUE-102
Leveraging the Immuno-STAT (Selective Targeting and Alteration of T cells) platform of targeted interleukin 2 (IL-2) therapies and the ongoing development of CUE-101, CUE-102 is being developed as a novel therapeutic fusion protein to selectively activate tumor antigen-specific T cells to treat Wilms’ Tumor 1 (WT1)-expressing cancers. CUE-102 consists of two human leukocyte antigen (HLA) molecules presenting a WT1 peptide, four affinity-attenuated IL-2 molecules, and an effector attenuated human immunoglobulin G (IgG1) Fc domain.

About the Neo-STAT and RDI-STAT (Re-Directed Immuno-STAT) Platforms
Immuno-STAT biologics are rationally engineered Fc fusion proteins comprised of bivalent tumor-peptide-human leukocyte antigen (pHLA) complexes and four affinity-attenuated interleukin 2 (IL-2) molecules to preferentially engage and activate tumor-specific T cells directly in the patient. Building on the CUE-100 series framework, our Neo-STAT (NST) platform contains HLA molecules manufactured with an "empty" peptide-binding pocket, into which diverse tumor-peptides can be chemically conjugated, hence addressing tumor heterogeneity in a cost- and time-efficient manner. Our RDI-STAT (Re-Directed Immuno-STAT) platform further expands on the Immuno-STAT biologics by redirecting the pre-existing protective viral-specific T cell repertoire to target tumor cells via scFv moieties. RDI-STATs are designed to circumvent potential tumor escape mechanisms linked to HLA loss or defects in antigen-presenting pathways.

About SITC (Free SITC Whitepaper)
The Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) is the world’s leading member-driven organization specifically dedicated to improving cancer patient outcomes by advancing the science and application of cancer immunotherapy.

SITC is a 501(c)(3) not-for-profit medical professional society of influential research scientists, physician scientists, clinicians, patients, patient advocates, government representatives and industry leaders dedicated to improving cancer patient outcomes by advancing the science and application of cancer immunotherapy. Through educational programs that foster scientific exchange and collaboration, SITC (Free SITC Whitepaper) aims to one day make the word "cure" a reality for cancer patients everywhere.

Currently, SITC (Free SITC Whitepaper) has more than 4,650 members who represent over 35 medical specialties in 63 countries around the world.

Through emphasis on high-caliber scientific meetings; dedication to education and outreach activities; focus on initiatives of major importance in the field; and commitment to collaborations with like-minded domestic and international organizations, government and regulatory agencies, associations and patient advocacy groups, SITC (Free SITC Whitepaper) brings together all aspects of the cancer immunology and immunotherapy community.

On November 12, 2021 Senti Bio, a leading gene circuit company, reported results from SENTI-401, one of its preclinical stage oncology programs, that aims to more precisely target tumors while sparing healthy cells (Press release, Senti Biosciences, NOV 12, 2021, View Source [SID1234596740]). The poster presentation, which is on display starting today at the Annual Meeting of the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper), describes preclinical data from SENTI-401, a Logic Gated allogeneic, chimeric antigen receptor natural killer (CAR-NK) cell therapy development program for the treatment of colorectal cancer (CRC). The results support the Company’s vision of using gene circuits to create next-generation, "smart" cell and gene therapies with computer-like logic in human cells.

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!

Targeting of tumor-associated antigens, such as carcinoembryonic antigen (CEA), can result in severe clinical toxicities due to the killing of healthy epithelial cells whose cell surfaces also express CEA. This includes toxicity risk to cells in the colon and gastrointestinal tract as well as the lungs. SENTI-401 is designed to incorporate logic gating to target and kill CEA-expressing tumor cells, while preventing the killing of CEA-expressing healthy epithelial cells. The SENTI-401 NOT GATE pairs a CEA-targeting activating-CAR (aCAR) with an inhibitory-CAR (iCAR) that recognizes a safety antigen (SA) uniquely expressed in certain healthy gastrointestinal and lung epithelial cells. The SA was identified and validated through Senti Bio’s proprietary Bioinformatics-Driven Antigen Pairing (B-DAP) discovery platform. The poster highlights the SENTI-401 development program’s NOT GATE gene circuit technology as follows:

Killing of colorectal cancer cells:

Generated, tested and optimized anti-CEA CAR constructs for optimal performance in NK cells using Senti Bio’s Design-Build-Test-and-Learn (DBTL) platform.
Evaluated CAR-NK cells for anti-tumor activity, and demonstrated potent killing of CEA-expressing CRC target cells in vitro. A single dose of these CAR-NK cells also demonstrated anti-tumor activity in a human CRC xenograft model, reducing tumor burden in >33% of the treated mice.

Preservation of healthy cells:

iCAR suppressed aCAR mediated killing (p<0.05) in a SA-dependent manner without diminishing aCAR-mediated anti-tumor activity.
V-set and Immunoglobulin Domain Containing 2 (VSIG2), a membrane protein, was identified as the SA via Senti Bio’s B-DAP discovery platform and validated in healthy tissue samples. VSIG2 is uniquely expressed in CEA-positive healthy cells but not in tumor cells.
Used Senti Bio’s DBTL platform to evaluate multiple iCAR designs that utilize inhibitory domains that can selectively prevent CAR-mediated killing in an SA-dependent manner.

"Existing cancer therapies generally target only a single tumor-associated antigen, which means that they can only be used safely and effectively where that antigen is expressed primarily on tumor cells," said Alba Gonzalez, PhD, presenter of the abstract and Associate Director, Research at Senti Bio. "What is so exciting about our Logic Gating platform is the potential to advance a highly novel approach to CAR-NK based therapy that may more precisely treat colon cancer, and other solid tumors, with a reduced risk for on-target, off-tumor toxicities, thereby offering the potential to increase the therapeutic window and provide meaningful benefit to patients."

The abstract (Poster #116) is available on the SITC (Free SITC Whitepaper) website. The poster is available on the Senti Bio website.

About Logic Gating and NOT GATE Gene Circuits
Logic Gating gene circuits are designed to enable cell and gene therapies to control their therapeutic activity in response to the presence or absence of multiple disease biomarkers. NOT GATE gene circuits are one type of Logic Gates that are designed to widen the therapeutic window by enabling killing of cancer cells while preserving healthy cells. The NOT GATE functions by recognizing Safety Antigens on the cell surface, or antigens that are selectively expressed on healthy cells and not on cancer cells, thus limiting on-target, off-tumor killing. By protecting healthy cells, the NOT GATE has the potential to enable more effective on-target, on-tumor killing of tumor cells that express tumor-associated antigens.

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

On November 12, 2021 Biosight Ltd., a pharmaceutical development company developing innovative therapeutics for hematological malignancies and disorders, reported the initiation of a Phase 2 trial to evaluate aspacytarabine (BST-236), Biosight’s proprietary antimetabolite, as a second line treatment for patients with relapsed or refractory myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) (Press release, Advaxis, NOV 12, 2021, View Source;soc_trk=ma [SID1234595728]). The multi-center study will be conducted across 18 leading U.S. and Israeli sites including Memorial Sloan Kettering Cancer Center and The University of Texas MD Anderson Cancer Center.

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!

"Biosight has built a strong foundation of compelling data that suggests that aspacytarabine may serve as a more tolerable and effective standard of care treatment for patients with AML," said Dr. Ruth Ben Yakar, Chief Executive Officer of Biosight. "The initiation of this multi-center, U.S. based, Phase 2 study is an important step forward in the development of aspacytarabine, seeking to address unmet needs in the treatment of patients with relapsed or refractory AML and MDS. We are proud to be continuing our momentum in the clinic and look forward to collaborating with leading academic medical centers as we progress the study."

Eytan Stein, M.D., Hematologic Oncologist at Memorial Sloan Kettering Cancer Center and lead investigator of the study said "I’m encouraged by the results from Biosight’s Phase 2b trial to be presented at the 63rd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting. The efficacy achieved in a challenging population, across key measures including complete remission and MRD (-) rates, duration of response and overall survival, are noteworthy. Furthermore, these results were particularly impressive as they were achieved with a favorable safety and tolerability profile in patients who are unfit for intensive chemotherapy. Patients with relapsed or refractory AML and MDS have limited treatment options and poor prognoses, with many patients unable to tolerate intensive chemotherapy. I look forward to leading this new Phase 2 study to evaluate the potential of aspacytarabine which may ultimately become the standard of care for relapsed or refractory MDS and AML patients for whom currently there are no effective treatments."

The Phase 2 open label multi-center study will assess the safety and efficacy of BST-236 as a single agent in adult patients unfit for standard therapy with AML or higher-risk (HR)MDS who fail to respond to, or have relapsed following, first line therapy. A similar study in patients with relapsed/refractory AML and MDS is ongoing in collaboration with the European cooperative group, Groupe Francophone des Myélodysplasies (GFM). Approximately 40 adult patients with relapsed and/or refractory AML and approximately 40 adult patients with relapsed and/or refractory HR MDS will be enrolled into the two studies. Primary endpoints include complete remission (CR) rate in AML patients and Overall Response Rate (ORR) in MDS patients, with ORR defined as the proportion of patients who achieve a CR or partial response (PR) per proposal for modification of the International Working Group (IWG) criteria for MDS, 2006.

About Aspacytarabine (BST-236)

Aspacytarabine is a novel proprietary anti-metabolite. It is composed of cytarabine covalently bound to asparagine, acting as a pro-drug of cytarabine. Cytarabine has served as the backbone of AML therapy for over 45 years due to its superior efficacy. However, it is associated with severe bone marrow, gastrointestinal, and neurological toxicities, which significantly limit its use, especially in older and medically compromised patients. Due to its unique pharmacokinetics and metabolism, aspacytarabine enables high-dose therapy with lower systemic exposure to free cytarabine and relative sparing of normal tissues. As such, aspacytarabine may serve as a new therapy for AML and other hematological malignancies and disorders, including for older adults who are unfit for intensive therapy.

Aspacytarabine was granted FDA Fast Track Designation for treatment of AML patients unfit for standard chemotherapy, and FDA and EMA Orphan Drug Designations, which entitle Biosight to seven and ten years of market exclusivity in the U.S. and Europe, respectively, upon aspacytarabine marketing approval for the treatment of AML in each territory.

Interim results from an ongoing Phase 2b study evaluating aspacytarabine as a single-agent first-line AML therapy demonstrate safety and single-agent activity, and additional studies are ongoing to evaluate aspacytarabine as a second line treatment for patients with relapsed or refractory MDS or AML. For more information regarding the Phase 2b clinical study of BST-236, please visit www.clinicaltrials.gov.