On April 7, 2024 Affini-T Therapeutics, Inc., a precision immunotherapy company unlocking the power of T cells against oncogenic driver mutations, reported that management is presenting data from the company’s oncogenic driver programs targeting HLA-A*11:01 KRAS G12D and HLA-A*02:01 p53 R175H at this year’s American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2024 in San Diego (Press release, Affini-T Therapeutics, APR 7, 2024, View Source [SID1234641850]). In addition, the team is presenting two trial-in-progress posters for Affini-T’s Phase 1 clinical-stage programs targeting KRAS G12V, the company-sponsored AFNT-211 study and the Fred Hutchinson Cancer Center investigator-initiated AFNT-111 study at AACR (Free AACR Whitepaper).

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 excited to be at AACR (Free AACR Whitepaper) unveiling new preclinical data, which includes a closer look at the promise of our novel non-viral TRAC-knocked-in T cell therapy for the treatment of p53 R175H-mutant solid tumors," said Loïc Vincent, Ph.D., Chief Scientific Officer, Affini-T Therapeutics. "We are also proud to present preclinical data from our cell therapy targeting KRAS G12D, which highlights the promising potential of our proprietary non-viral knock-in THRIVE platform. These findings continue to motivate our team as we advance programs leveraging TCR-engineered T cells as potential paradigm-shifting treatments for patients with solid tumor cancers."

Poster presentation details are as follows:

AFNT-212: A TRAC-knocked-in KRAS G12D-specific TCR-T cell product enhanced with CD8αβ and a chimeric cytokine receptor for treatment of solid cancers

Abstract #5973, Session: Adoptive Cell Therapies 1: Tumor Antigen-Specific T-cells and TCR-T
Session Date/Time: Sunday, April 7, 2024, 1:30 PM – 5:00 PM
Presenting Author: Loïc Vincent, Ph.D., Chief Scientific Officer, Affini-T Therapeutics
Summary: AFNT-212-engineered TCR-T cells showed high functional avidity and in vitro cytotoxicity against KRAS G12D-positive tumor cell lines, including CL40 (colon), PANC-1 and HPAF-II (pancreas), SK-LU-1 (lung), HuCCT1 (cholangiocarcinoma), etc. Additionally, engineered TCR-T cells demonstrated robust and durable anti-tumor activity in vivo and low risk of off-target/off-tumor toxicity. Affini-T’s proprietary non-viral knock-in (KI) THRIVE platform achieved high transgene integration efficiency and cell growth to yield relevant numbers of engineered TCR-T cells for clinical application. The study supports the planned clinical investigation of the novel KRAS G12D mutant TCR-engineered CD4+ and CD8+ T cell therapy in 2024.
Non-viral engineered T cell therapy specific for the hotspot mutation p53 R175H that integrates signal 1 (TCR), signal 2 (co-stimulation) and signal 3 (cytokine) and co-opts FasL-dependent apoptosis to achieve a coordinated antitumor CD4/8 T cell response

Abstract #7242, Session: Adoptive Cell Therapies 1: Tumor Antigen-Specific T-cells and TCR-T
Session Date/Time: Sunday, April 7, 2024, 1:30 PM – 5:00 PM
Presenting Author: Gary Shapiro, Ph.D., VP Biology Discovery, Affini-T Therapeutics
Summary: The tumor suppressor TP53 is the most frequently mutated gene across human cancers, with a highly recurrent arginine to histidine hotspot alteration in codon 175 leading to novel tumor-dependent functions. In this study, we reported the use of a novel CRISPR-Cas nuclease system to knock in a six-gene multi-cistronic cassette into the TRAC locus with high efficiency. We employed several strategies to maximize the potency and durability of a TCR-T cell product targeting the p53 R175H oncogenic driver, TCR, co-stimulation and cytokine signaling – which delivered full stimulation of both CD8+ and CD4+ T cells. These data support the planned clinical development of a novel non-viral TRAC-knocked-in T cell therapy for the treatment of p53 R175H-mutant solid tumors.

On April 7, 2024 Edgewood Oncology, a clinical-stage biotechnology company focused on delivering BTX-A51 to patients with hematologic malignancies and genetically-defined solid tumors, reported the publication of new preclinical data from a study of BTX-A51 in human liposarcoma (LPS) conducted by Dana-Farber Cancer Institute and Hebrew University-Hadassah Medical School to be presented at the AACR (Free AACR Whitepaper) Annual Meeting 2024 in San Diego (Press release, Edgewood Oncology, APR 7, 2024, View Source [SID1234641851]). BTX-A51 is a first-in-class, small molecule, multi-selective kinase inhibitor of casein kinase 1 alpha (CK1α) as well as the transcriptional regulators cyclin-dependent kinases 7 and 9 (CDK7 and CDK9) that synergistically co-targets master regulators of cancer to promote programmed cell death, or apoptosis.

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 presentation (Abstract 604), "Targeting casein kinase 1 alpha (CK1alpha) and transcriptional CDKs (CDK7/9) in human liposarcomas," highlighted findings for BTX-A51 in preclinical human models of LPS. The data demonstrate that BTX-A51 has preclinical efficacy in treating patient-derived LPS in cell lines and human xenograft models and provides insight into the synergy gained by inhibiting both CK1α and CDK9.

"Dedifferentiated liposarcomas (DDLPS) are rare tumors derived from precursors of fat cells which can occur anywhere in the body. Patients with metastatic DDLPS face a life-threatening disease in need of more effective therapeutic options, which we hope to develop by taking advantage of vulnerabilities in LPS that have been uncovered by recent research on the abnormal DNA and other molecular characteristics of LPS," said George Demetri, M.D., Professor of Medicine and director of the Sarcoma Center at Dana-Farber. "Based on these data, we believe that it is justified to move BTX-A51 into a clinical trial for patients with LPS, which we will plan to open soon for enrollment."

Liposarcomas are universally characterized by amplification of the mouse double minute 2 homolog (MDM2) gene, which leads to destruction of the normal (non-mutated, also known as "wild type") p53. The data demonstrate that BTX-A51 significantly reduces the abnormal overexpression of MDM2 in multiple patient-derived LPS cell lines, leading to upregulation of p53 expression and ultimately apoptosis. Finally, BTX-A51 was demonstrated to be well-tolerated and effective in an LPS patient-derived xenograft model.

"We’re pleased that investigators at Dana-Farber have taken an interest in BTX-A51, which is currently being evaluated in a Phase 2 combination study with azacitidine in patients with relapsed or refractory (R/R) AML," said David N. Cook, Ph.D., chief executive officer of Edgewood Oncology. "These data also suggest the potential for BTX-A51 in cancers with MDM2 amplifications, a group of genetically defined tumors that span multiple tissue types suggesting broader potential."

Additional Details about the Study

Using three different CDK9-selective inhibitors in human LPS cell lines, the authors showed that CDK9 inhibition suppressed cell growth and induced apoptosis by decreasing MDM2 levels while inducing expression of p53. It was also demonstrated that the potency of CDK9 inhibitors is significantly enhanced upon CK1α depletion. These data led to the investigation of BTX-A51, which targets CK1α and CDK9 as well as CDK7, in LPS cells and has previously been shown to inhibit these kinases with nanomolar efficacy in AML models. BTX-A51 potently reduced expression of MDM2 with marked induction of p53, resulting in apoptosis of LPS cells. BTX-A51 also reduces expression of MCL1 and primes LPS cell lines and primary LPS cells for BIM-induced apoptosis, as demonstrated by BH3 profiling. Importantly, preliminary in vivo data in an LPS patient-derived xenograft model reveal that BTX-A51 is well-tolerated under conditions that inhibit tumor growth.

On April 7, 2024 BioNTech SE (Nasdaq: BNTX, "BioNTech" or "the Company") reported three-year follow-up data from a Phase 1 trial with the mRNA-based individualized neoantigen-specific immunotherapy ("iNeST") candidate autogene cevumeran (also known as BNT122, RO7198457) in patients with resected pancreatic ductal adenocarcinoma ("PDAC") (Press release, BioNTech, APR 7, 2024, View Source [SID1234641837]). The data show that in 8 out of 16 patients autogene cevumeran elicited an immune response up to three years post administration measured by activated T cells. The persistence of T cels was associated with a longer median recurrence-free survival in cancer vaccine responders.

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!

"These new data are an early signal for the potential of our individualized mRNA cancer vaccine approach in this indication with an unmet medical need. The results indicate that our uridine mRNA-LPX technology can promote activation of cytotoxic T cells that may help to eliminate residual tumor foci at early stages of the disease to delay or prevent recurrence," said Prof. Özlem Türeci, M.D., Co-Founder and Chief Medical Officer at BioNTech. "Our ongoing Phase 2 trial with Genentech aims to confirm these findings on benefit for patients with PDAC compared with the current standard of care treatment in the post-surgical, adjuvant setting in a larger patient population. We remain committed to our vision of personalized cancer medicine and aim to help advance the standard of care for many patients."

The results featured in an oral presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) ("AACR") Annual Meeting 2024 show the following:

In 8 of 16 patients, autogene cevumeran elicited high-magnitude T cells specific to the encoded neoantigens.
98% of the T cells targeting individual neoantigens on the tumor and induced by autogene cevumeran were de novo in that they were not detected in blood, tumors, and adjacent tissues prior to administration of the investigational treatment.
Over 80% of the vaccine-induced neoantigen-specific T cells could still be detected up to three years post administration in patients with an immune response. These patients showed a prolonged median recurrence-free survival compared to non-responders.
6 of 8 patients with an immune response to autogene cevumeran remained disease free during the three-year follow-up period, while 7 of the 8 patients without an immune response to the treatment during the trial showed tumor recurrence.
The investigator-initiated, single center Phase 1 trial (NCT04161755) evaluated the safety of autogene cevumeran in sequential combination with the anti-PD-L1 immune checkpoint inhibitor atezolizumab and standard-of-care chemotherapy in 16 patients with resected PDAC. Data from the 1.5-year median follow-up were published in Nature in May 2023. The current data update includes a three-year median follow-up and was presented in a late-breaking oral presentation at the AACR (Free AACR Whitepaper) Annual Meeting 2024 in San Diego, California, by principal investigator Vinod Balachandran, M.D., surgeon-scientist at Memorial Sloan Kettering Cancer Center and principal investigator of the study.

An ongoing open-label, multicenter, randomized Phase 2 trial (NCT05968326), sponsored by Genentech in collaboration with BioNTech, was started in October 2023. The trial will investigate the efficacy and safety of adjuvant autogene cevumeran in combination with the anti-PD-L1 immune checkpoint inhibitor atezolizumab and chemotherapy compared with the current standard of care chemotherapy (mFOLFIRINOX) in patients with PDAC. The Phase 2 trial is currently enrolling patients at clinical trial sites in the United States, with additional sites planned to open globally. Autogene cevumeran is being jointly developed by BioNTech and Genentech and is currently being evaluated in three ongoing randomized Phase 2 clinical trials in adjuvant PDAC (as mentioned above), first-line melanoma, and adjuvant colorectal cancer.

About resected pancreatic ductal adenocarcinoma (PDAC)
PDAC is amongst the leading causes of cancer-related deaths in the United States4 with approximately 90% of patients dying within two years of their diagnosis5. A combination of surgical removal and systemic cytotoxic chemotherapy has shown to improve clinical outcomes; however, even with surgical resection, the relapse rate remains high, and the 5-year overall survival is only approximately 20%6 in patients who undergo surgery followed by adjuvant chemotherapy ("ACT") and only 8-10%i,ii in those who do not receive ACT. Thus, there is an unmet medical need for novel therapies for patients with resected PDAC.

About iNeST (individualized Neoantigen Specificimmuno Therapy)
iNeST immunotherapies are investigational individualized cancer therapies tailored to a specific patient’s tumor. They contain unmodified, pharmacologically optimized mRNA encoding up to 20 patient-specific neoantigens, identified using real-time next-generation sequencing and bioinformatic neoantigen discovery. Neoantigens are proteins that are produced by cancer cells that differ from the proteins produced by healthy cells and are recognized by immune cells. The mRNA is encapsulated in BioNTech’s proprietary intravenous RNA-lipoplex delivery formulation which is designed to enhance stability as well as enable targeted delivery to dendritic cells. By analyzing each patient’s tumor, BioNTech is able to identify the cancer mutations that may act as neoantigens. Each individual cancer vaccine encodes for neoantigen candidates with the highest likelihood of helping the immune system recognize the cancer. For this purpose, BioNTech has developed an on-demand manufacturing process, following Good Manufacturing Practice (GMP) conditions. Autogene cevumeran is currently being evaluated in various solid tumor indications, including three Phase 2 clinical trials in first-line melanoma, adjuvant colorectal cancer, and adjuvant pancreatic ductal adenocarcinoma.

An iNeST Fact Sheet and images from the iNeST manufacturing process are available in the newsroom section on BioNTech’s website at this link.

On April 7, 2024 HiFiBiO Therapeutics, a leading clinical stage global biotechnology company committed to advancing patient outcomes through single-cell precision, reported two posters at the AACR (Free AACR Whitepaper) 2024 meeting held on April 5-10, 2024, in San Diego, CA (Press release, HiFiBiO Therapeutics, APR 7, 2024, View Source [SID1234641870]).

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!

"One of the major challenges cancer immunotherapies face is the difficulties in selecting patients with tumors that will respond. Single-cell technologies can provide valuable insights into disease biology and help discern tumors that are more likely to respond; however, the lack of integrated data across diverse single-cell platforms hinders the potential of these novel technologies to inform clinical decisions." Jack Russella-Pollard, Ph.D., Executive Director, Translational Data Science, commented, "HiFiBiO has built an AI/ML powered curation and data integration process within our Drug Intelligence Science (DIS) translational platform that integrates publicly available datasets with in-house generated datasets to predict tumor response and guide target as well as indication selection."

Jinping Gan, Ph.D., Vice President, Global Head of Research, remarked: "Currently, there is no suitable model to describe complex tumor-immune interactions that can effectively guide clinical decisions. HiFiBiO has successfully constructed semi-mechanistic PKPD models for an anti-TNFR2 agonist and an anti-OX40 agonist that advocate for pulsatile agonism to achieve optimal anti-tumor efficacy. This innovative scientific work serves as a valuable tool for guiding dose and dose regimen optimization for the humanized versions of these T cell co-stimulatory agonists in clinical development."

By harnessing these cutting-edge technologies and tools within its DIS platform, HiFiBiO Therapeutics is steering the development of its drug candidates, including three antibodies currently undergoing Phase 1 evaluation: a first-in-class TNFR2 agonist (HFB200301, NCT05238883), a next-generation OX40 agonist (HFB301001, NCT05229601), and a best-in-class BTLA antagonist (HFB200603, NCT05789069).

These presentations underscore HiFiBiO Therapeutics’ unwavering commitment to innovation and its relentless pursuit of novel therapeutic solutions to address unmet medical needs.

Details on the poster presentations are as follows. E-Posters will be posted on HiFiBiO’s website following the live presentations.

Abstract Number: 6202

Title: Integrating public single-cell transcriptomics and patient profiles to guide clinical development

Presenter: Jack Russella-Pollard, Ph.D., Executive Director, Translational Data Science
Session Category: Bioinformatics / Computational Biology / Systems Biology / Convergent Science

Session Title: Integrative Cancer Science

Session Date and Time: Tuesday Apr 9, 2024, 1:30 PM – 5:00 PM

Location: Poster Section 36

Poster Board Number: 5

View full abstract here.

Abstract Number: 7176

Title: Optimization of T cell co-stimulatory agonists: A semi-mechanistic PKPD model integrating drug properties and tumor-immune interactions

Presenter: Jinping Gan, Ph.D., Vice President, Global Head of Research

Session Category: Experimental and Molecular Therapeutics

Session Title: Pharmacology and Pharmacogenetics

Session Date and Time: Wednesday Apr 10, 2024, 9:00 AM – 12:30 PM

Location: Poster Section 24

Poster Board Number: 17

View full abstract here.

On April 5, 2024 Bold Therapeutics, a clinical-stage biopharmaceutical company at the forefront of developing innovative metallotherapeutics, reported that Dr. Do-Youn Oh’s group at Seoul National University College of Medicine, Seoul, South Korea, will be presenting at the AACR (Free AACR Whitepaper) Annual Meeting, April 5-10, 2024, in San Diego, California on the use of BOLD-100 in combination with ATR (Ataxia telangiectasia and Rad3-related protein serine/threonine kinase) inhibitors as anticancer therapies for the treatment of Pancreatic Ductal Adenocarcinoma (PDAC) (Press release, Bold Therapeutics, APR 5, 2024, View Source [SID1234641821]).

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!

Bold Therapeutics’ BOLD-100, a pioneering ruthenium-based small molecule, uniquely acts by (1) targeting GRP78 to modulate the unfolded protein response (UPR) and (2) generating reactive oxygen species (ROS) leading to DNA damage and cell cycle arrest. This dual action triggers cell death across a spectrum of cancer types, including those resistant to current treatments. As a result, BOLD-100 holds promise for significantly enhancing treatment outcomes in a diverse array of both solid and liquid tumors when used alongside a broad range of anticancer treatments, from conventional chemotherapies to cutting-edge targeted therapies and immuno-oncology agents. Our recent presentation at ASCO (Free ASCO Whitepaper) GI 2024 showcased positive Phase 2 clinical trial results in the treatment of advanced metastatic colorectal cancer (mCRC) in patients previously treated with FOLFOX / CAPOX. The data, highlighting patients treated with a combination of BOLD-100 and FOLFOX, demonstrated notable safety and clinical improvements, bolstering confidence in the therapeutic value of BOLD-100.

Dr. Do-Youn Oh’s group at Seoul National University College of Medicine, South Korea will be presenting a poster entitled, "Co-downregulation of GRP78 and ATR enhances apoptosis in pancreatic ductal adenocarcinoma," (Poster no. 12, Session: Cellular Stress Responses 1). This work underscores the significant impact of BOLD-100 in inducing GRP78 inhibition, which substantially triggers oxidative stress. Furthermore, when combined with ATR inhibition, this synergy effectively promotes cell death.

Key Findings:

BOLD-100 elevates ER stress and ROS, leading to activation of the UPR pathway and CHOP-dependent apoptosis, which inhibits PDAC growth;
ROS accumulation activates the ATR-CHK1 DNA damage repair pathway, which NAC can abrogate; and
The combination of BOLD-100 with the ATR inhibitor AZD6738 exhibits a synergistic effect, suggesting GRP78/ATR dual targeting as a promising therapeutic approach for PDAC.
These findings unveil a compelling strategy for combinational targeting to inhibit PDAC growth.

"DNA repair mechanisms play a crucial role in maintaining genomic integrity, leading to cell cycle arrest and thereby preventing the uncontrolled growth and progression of cancer cells. Our in-vitro and in-vivo findings indicate that combining BOLD-100 with ATR inhibition results in synthetic lethality against highly aggressive Pancreatic Ductal Adenocarcinoma. We are eager to delve deeper into this research path and its potential clinical utility," stated Dr. Oh.

Mark Bazett, Sr Director, Preclinical Development at Bold Therapeutics added, "BOLD-100 has already demonstrated remarkable safety and efficacy in the treatment of metastatic colorectal cancer (mCRC). Diverging from the path of targeted therapies, BOLD-100’s unique multi-modal mechanism-of-action opens avenues for potent combination therapies designed to tackle some of the most difficult-to-treat cancers including those resistant to standard treatments. The synergistic combination identified by Dr. Oh’s group holds particular promise, and we look forward to further exploring this potential."

Jim Pankovich, EVP, Clinical Development at Bold Therapeutics, and Mark Bazett, Sr Director, Preclinical Development at Bold Therapeutics, will also be attending the 2024 AACR (Free AACR Whitepaper) Annual Meeting in San Diego and are available for in-person discussions related to BOLD-100.

For additional details, visit Bold Therapeutics’ website at www.bold-therapeutics.com or the AACR (Free AACR Whitepaper) conference site at View Source