News from AACR 2024: Monday’s highlights

San Diego

A round-up of the latest news from the American Association of Cancer Research (AACR) Annual Meeting.

Symposiums

UCLA: Dr Zev Wainberg, Co-Director of the UCLA Health GI Oncology Program, presented results from pilot study led by UCLA Health Jonsson Comprehensive Cancer Center investigators, which suggests that for people with borderline resectable pancreatic cancer, administrating an immunotherapy drug in combination with chemotherapy before surgery is safe and may improve long-term outcomes. The findings showed that treating patients with the combination therapy prior to surgery resulted in a higher rate of successful tumour removal, increased the period of time before the cancer worsened, and extended overall survival when compared to historical controls. The researchers also found that adding the immunotherapy component did not increase significant adverse side effects and led to no significant post-operative complications.

Accent Therapeutics: Robert Copeland, Chief Scientific Officer, Accent Therapeutics, gave a symposium presentation on RNA-modifying enzyme inhibitors as precision cancer therapeutics and detailed the rationale for DHX9 inhibition as a novel treatment modality for patients with BRCA1/2 loss-of-function across multiple tumour types, including breast cancer, as well as dMMR/MSI-H tumours, including colorectal, gastric and endometrial cancers.

The company also presented poster sessions supporting inhibition of KIF18A in chromosomally instable tumours and induction of circBRIP1 RNA as a biomarker for DHX9 inhibition.

Poster sessions

The Annual Meeting had a record number of submitted poster abstracts this year. Here’s a few highlights.

Mythic Therapeutics presented pre-clinical data for its cMET-targeting antibody-drug conjugate (ADC) MYTX-011. In the studies presented, the pH-engineered antibody component of MYTX-011 demonstrated markedly increased accumulation in cancer cells expressing high, moderate or low cMET levels compared to its matched non-engineered parent antibody. MYTX-011 demonstrated broader and more potent cMET-dependent cytotoxicity across a panel of cancer cell lines compared to a matched parent ADC. MYTX-011 was shown to be highly active in cMET+ xenograft models derived from gastric, oesophageal and head and neck cancers.

Vincerx Pharma debuted positive preliminary Phase I data for its VIP236 programme in heavily pretreated patients with metastatic tumours. Fifteen patients have been dosed to date, seven of which have achieved objective stable disease including tumour reduction. Data show it is well tolerated and additional Phase I data is anticipated this summer.

Quanta Therapeutics gave a late-breaking poster presentation of QTX3544, a KRASG12V-preferring multi-KRAS inhibitor with favourable preclinical properties, including potency, selectivity, and oral bioavailability. The company’s allosteric approach has the potential to target the majority of KRAS mutations with a robust mechanism of action addressing multiple conformations of KRAS.

Immunitas Therapeutics presented pre-clinical data supporting the combination potential of its anti-CD161 antibody IMT-009 with anti-PD1 immunotherapy. IMT-009 has been shown to restore the anti-cancer activity of T and NK cells in pre-clinical studies by blocking interactions between CD161 and its ligand, CLEC2D, and is currently undergoing clinical evaluation for use in solid tumour and haematologic malignancies. In cancer cell models, the combination of IMT-009 and anti-PD1 treatment significantly enhanced T cell mediated tumour killing.

Poseida Therapeutics announced new data from a subset of patients in an ongoing Phase I study of its lead programme, P-BCMA-ALLO1. P-BCMA-ALLO1 is a novel investigational B-cell maturation antigen (BCMA)-targeted allogeneic, T stem cell memory (TSCM)-rich chimeric antigen receptor T-cell (CAR-T) therapy manufactured from healthy donor T-cells and available off-the-shelf. Results showed that three of the five (60%) patients with relapsed/refractory multiple myeloma who had progressed following BCMA-targeted therapy achieved clinical responses with P-BCMA-ALLO1.

Precision Biologics reported its lead monoclonal antibody, NEO-201, targets circulating human naïve regulatory T cells (Tregs) in both healthy donors and cancer patients. Human PBMCs were collected from seven healthy donors (HD) at Osaka University and six cancer patients from Precision Biologics ongoing Phase II clinical trial evaluating the efficacy of the combination of NEO-201 with pembrolizumab in adults with solid tumours resistant to checkpoint inhibitors. Flow cytometry analysis revealed that NEO-201 recognises fraction I of CD4 T cells in both healthy donors and cancer patients. The study suggests therapy with NEO-201 may reduce Treg-mediated suppression of anticancer immunity.

Hinge Bio: Daniel Capon, Chief Scientific Officer, and Juha Punnonen, Chief Development Officer, Hinge Bio, presented data from the company’s GEM-DIMER programme targeting B cell depletion. The data indicated CD19/CD20-targeting GEM-DIMER molecules are promising candidates to provide efficient depletion of both CD19+ and CD20+ cells, providing potential for broad and deep depletion of B cells with reduced risk of emergence of antigen escape variants. This supports the advancement of these CD19/CD20-targeting GEM-DIMER molecules in multiple indications where depletion of CD19+ and/or CD20+ B cells is needed.

Pyxis Oncology presented on PYX-106 (BSI-060T), a humanized anti-Siglec-15 monoclonal antibody being developed for solid tumours, including for patients that are not candidates for anti-PD-(L)1 treatment approaches. In the research, analysis of Siglec-15 mRNA expression was performed across single cells, cell lines, and bulk tumour samples to evaluate Siglec-15 target expression across a range of cancer types, including non-small cell lung cancer (NSCLC), cholangiocarcinoma, breast, thyroid, head and neck, colon, rectal, bladder, kidney, and endometrial cancers. The results demonstrate that Siglec-15 and PD-L1 are rarely found co-expressed on the same cell, provide detailed data on Siglec-15 and PD-L1 expression patterns by cancer type, and are expected to help inform potential future PYX-106 (BSI-060T) therapeutic strategies.

Biosion presented three posters on its oncology pipeline, including BSI-111, an anti-CD16a monoclonal antibody, BSI-730, a HER2/PD-L1 bispecific antibody and BSI-093, an anti-BTN3A monoclonal antibody. BSI-111 binds specifically to CD16a without recognising CD16b and binds the two allelic variants of CD16A – 158F and 158V with similar high affinity. It demonstrates superior biophysical properties and functional characteristics, supporting the development of anti-CD16a-based NK cell engagers for the potential benefit of cancer patients. BSI-730 has shown comparable binding affinity to HER2 as compared to trastuzumab, as well as comparable bioactivity to the parental anti-PD-L1 antibody regarding PD-L1 binding and PD-1/PD-L1 blocking. The BTN3A family including BTN3A1, BTN3A2 and BTN3A3 are members of the Ig superfamily receptors, and is essential for the activation of Vγ9Vδ2 T cell-mediated anti-tumour immune responses. BTN3A’s expression is significantly higher in tumour samples of cholangiocarcinoma, oesophageal carcinoma, head and neck squamous cell carcinoma, compared to their counterpart normal tissue controls.

STORM Therapeutics: Alexandra Sapetschnig, Group Leader at STORM, presented late breaking data on STORM’s METTL1 inhibitors, detailing the discovery of STORM’s first-in-class inhibitors of METTL1 tRNA methyltransferase and supporting evidence of its potential as a novel target for anti-cancer drugs.

Biond Biologics presented on BND-35, a humanized IgG4, ILT3 (LILRB4) antagonist antibody, designed to modulate the tumour microenvironment (TME) from immunosuppressive to pro-inflammatory, thereby counteracting tumour growth. Pivotal research on BND-35 demonstrates its specificity in binding ILT3 with high affinity, without affecting other ILT-family receptors. The specific blocking of ILT3’s interaction with key ligands significantly enhances the pro-inflammatory activity of myeloid cells and effectively reverses ILT3-mediated immune suppression of T cells. The presentation detailed how BND-35, as a standalone therapy and in combination with anti-PD-1 and anti EGFR agents, has shown promising results in restoring T and NK cell activity and inducing a pro-inflammatory TME in various in vitro, ex vivo, and in vivo models.

Adcentrx Therapteutics presented pre-clinical data for its lead ASC programme ADRX-0706, a novel fully human IgG1 antibody targeting human Nectin-4 linked to a novel tubulin inhibitor payload, AP052, in three poster presentations. The preclinical data showed an improved therapeutic window of ADRX-0706, enhanced bystander effect and improved payload delivery to Nectin-4 expressing tumours while minimising exposure to normal tissues.

IRBM disclosed new data on two of its most promising internal assets. Potential first-in-class ADC targeting CRLF2/TLSPR in “Ph-like” B-ALL (AM E3-SG3249) demonstrated significant pre-clinical efficacy, representing a pioneering approach to treating haematologic cancer characterized by poor prognosis and high relapse rates, often affecting adolescents. Brain permeable SHP2 allosteric inhibitor (I-1000233) exhibited promising results in pre-clinical studies, offering a new method of treating patients with RAS-driven malignancies, including challenging brain tumours and metastases.

Myeloid Therapeutics provided a pre-clinical update for MT-302, its novel TROP2-targeting RNA CAR, which is currently in a Phase I study to assess the therapy’s safety and activity in patients with advanced or metastatic epithelial tumours. To date, Myeloid has demonstrated CAR activity in human cells, and following systemic mRNA/LNP delivery in mouse and non-human primates.

Myeloid’s portfolio also includes a set of novel CARs designed specifically to programme NK and T cells. The programmed NK cells induce cytotoxicity against antigen-expressing tumour cells and trigger the release of cytokines and chemokines, important factors to a full immune response. The company further demonstrated that this approach can be used to design receptors for selective expression on the surface of T cells utilising CD3𝜀 chain fused with tumour-targeting scFv.

Ascentage Pharma released the latest results from three pre-clinical studies. Olverembatinib, a novel multi-kinase inhibitor, showed superior anti-tumour activity in dSDH cell lines in vitro and human dSDH GIST primary tumour cells ex vivo. It exerted anti-tumor effects by modulating multiple signalling pathways including hypoxia, angiogenesis, apoptosis, proliferation, and survival, which are involved in tumorigenesis of dSDH cancers.

Embryonic ectoderm development (EED) inhibitor APG-5918 (EEDi-5273) and MDM2 inhibitor alrizomadlin (APG-115) synergistically inhibit tumour growth in preclinical models of prostate cancer (PCa). PD analysis revealed that APG-5918 downregulated the oncogenic DNA methylation factors (UHRF1, DNMT1) and histone methylation marker H3K27me3. Alrizomadlin markedly downregulated UHRF1 and DNMT1, and upregulated p53 and p21 expression. Combined treatment further enhanced downregulation of DNMT1, UHRF1, cell cycle pathway proteins (pRb, CDK6), antiapoptotic protein MCL-1, and synergistically increased cleavage of PARP-1, a marker of apoptosis.

Diana Spencer, Senior Digital Content Editor, DDW

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