MB-388 Enters Clinic Behind AC484 With No Efficacy Precedent to Anchor

LAG-3-resistant CAR T cells for breast cancer: two complementary bioengineering strategies are described as (1) armored CAR T cells engineered to secrete anti-LAG-3 antibody fragments locally within the TME, and (2) CAR T cells modified to express dominant-negative LAG-3 receptors or with LAG-3 genetically ablated, conferring intrinsic resistance to this inhibitory axis upon engagement with ligands such as MHC class II.

PD-1/CTLA-4 bispecific antibody plus chemotherapy: cadonilimab (10 mg/kg) and chemotherapy (docetaxel, 75 mg/m2 plus cisplatin, 60 mg/m2) every 3 weeks for three cycles in locally advanced, resectable head and neck squamous cell carcinoma showed ORR was 83.3%, DCR was 100.0%, MPR rate was 76.7% and PCR rate was 50.0%, with Grade 3 TRAEs reported in 7 (23.3%) patients.

PD-1-CD28-enhanced receptor plus CD19 CAR-modified TILs: S-TILs (TILs modified through transduction with a plasmid encoding the PD-1-CD28-T2A-CD19 CAR) were evaluated in vivo, with PD-1-CD28-TCR-T cells showing anti-tumor ability that was not subject to PD-1/PD-L1 signaling, and CD19 CAR-TCR-T cells stimulated with CD19 B cells exhibiting expansion and anti-tumor abilities; three patients with refractory solid tumors received S-TILs infusion with one melanoma partial response and two colon or kidney cancer long-term stable disease.

Microenvironment-responsive PD-L1 x CD3 engager: Protease-Activated PSTAGylated BiTE, named PAPB, includes a shielding polypeptide domain (PSTAG), a protease-activated linker, and a BiTE core consisting of two scFvs targeting PD-L1 and CD3, releasing BiTE core in response to MMP2 in the tumor microenvironment; plasma half-life in mice was prolonged from 2.46 h to 6.34 h of the BiTE core, with increased infiltration of T lymphocytes in A375 melanoma xenografts.

Cytotoxic lymphocyte-related targets including PTPN2 and LDHA in glioblastoma: a three-gene prognostic index (CTLsTKPI: LDHA, TNIP1, PTPN2) via Cox and LASSO stratified survival with AUCs 0.694/0.656/0.819 at 1/2/3 years, high CTLsTKPI aligned with checkpoint pathway activation, Treg/macrophage enrichment and reduced activated NK/CD8 T cells, and LDHA inhibition (GNE-140) synergised with PD-1 blockade to reduce tumour burden and prolong survival.

HER2-low and HER2-altered disease: Median incidences of HER2-low were 52%, 16%, 58%, and 17% in breast, gastro-oesophageal, endometrial, and ovarian cancers, respectively, with unknown incidences in lung and cervical cancers. Trastuzumab deruxtecan improves survival in both HER2-positive and HER2-low breast cancer patients, improves survival in HER2-positive gastro-oesophageal cancer and elicits objective responses in HER2-low tumours, with responses also noted in lung and gynaecological cancers with HER2 expression. Trastuzumab deruxtecan received regulatory approval as the first targeted therapy for pre-treated, HER2-mutant, advanced NSCLC patients based on DESTINY-Lung01 and DESTINY-Lung02 trials, and received accelerated approval for advanced, pre-treated HER2-positive solid tumours with no other treatment options.

CLDN18.2-positive advanced gastric or gastro-oesophageal junction cancer: Patients with CLDN18.2-positive (immunohistochemistry expression intensity ≥2+ and positive tumour cells ≥40%) advanced gastric or gastro-oesophageal junction cancer, who were refractory to at least two previous lines of treatment, were targeted with satricabtagene autoleucel (satri-cel; also known as CT041) versus treatment of physician's choice. Median progression-free survival was 3·25 months (95% CI 2·86-4·53) in the satri-cel group and 1·77 months (1·61-2·04) in the TPC group (hazard ratio 0·37 [95% CI 0·24-0·56]; one-sided log-rank p<0·0001). CMG901, a humanised anticlaudin 18.2 antibody linked to microtubule-disrupting agent monomethyl auristatin E, showed confirmed objective response rate of 28% (95% CI 20-38; 32 of 113 patients) in gastric or gastro-oesophageal junction cancer.

Microsatellite instability-high / mismatch repair-deficient and PD-L1-high tumours: Cohorts with microsatellite instability-high (MSI-H) tumours (n=41) and non-small cell lung cancer with high programmed death-ligand 1 expression (NSCLC/PDL1-H, tumour proportion score ≥50%) (n=13) were evaluated with AMG 404, with objective response rate (80% CI) of 36.6% (26.4-47.8) and 30.8% (14.2-52.3), respectively. In MSI/dMMR advanced pancreatic ductal adenocarcinoma, 15 (48.4%) had an objective response and median progression-free survival (PFS) was 26.7 months.

KRAS G12C, NTRK fusions, and TROP2-directed approaches: Adagrasib received first approval in the USA for adults with KRAS G12C-mutated locally advanced or metastatic NSCLC who have received ≥ 1 prior systemic therapy. NTRK fusions were detected in 0.71% (n = 12) of 1,687 patients, with larotrectinib and entrectinib approved as tumour-agnostic therapies for solid tumours harbouring NTRK fusions. Datopotamab deruxtecan, a trophoblast cell surface antigen 2 (TROP2)-directed antibody-drug conjugate, was approved for adult patients with unresectable or metastatic HR positive, HER2 negative breast cancer, while TROP2 is elevated during colorectal cancer metastatic process with high levels in liver metastases predicting increased post-therapy recurrence.

CNS involvement and immunotherapy-refractory gastrointestinal cancers: Leptomeningeal disease (LMD) with approximately 10-15% of patients with advanced malignant melanoma developing LMD, and brain metastases with median Overall Survival (OS) from BM diagnosis of 3 months (range: 0-127) in genito-urinary cancers and median OS from the diagnosis of brain metastases of 11.35 months across solid tumours. Metastatic gastrointestinal epithelial cancers with progressive disease following at least one first line standard therapy, including microsatellite-instability-high colorectal cancer refractory to anti-PD1/CTLA-4 therapies, were targeted with neoantigen-reactive CISH-knockout tumour infiltrating lymphocytes, with one complete and ongoing response (>21 months).