Clinical Cancer Research最新文献

Purpose: Adenosine signaling may be a central immunosuppressive mechanism in several cancers, and blockade of the rate-limiting CD73 adenosine monophosphate (AMP)-to-adenosine enzyme has been demonstrated to improve the clinical efficacy of programmed cell death protein (ligand) 1 [PD-(L)1] immune therapy. However, deep inhibition of CD73 activity could prove difficult in tumor environments with a constant AMP supply and high CD73 levels. In this study, we sought to identify, characterize, and benchmark a novel antagonistic anti-CD73 antibody, Sym024 (S95024), and to structurally decode its mode of action.

Experimental design: Sym024, selected via functional antibody repertoire screening, was tested against benchmark anti-CD73 antibodies in primary cell, cell line in vitro binding, CD73 enzymatic activity, and T-cell activation assays. Its in vivo tumor growth inhibition was examined in transplanted human or mouse tumors in immunocompetent or immunodeficient mice, and intratumoral enzymatic inhibition and immune cell recruitment were assessed. We investigated the Sym024-CD73 interaction using surface plasmon resonance, cryogenic electron microscopy, site-directed mutagenesis, and population-level complex formation through size-exclusion chromatography with light scatter mass detection. Preclinical safety and pharmacokinetics (PK) were assessed in monkeys.

Results: Sym024 effectively blocked CD73 across a large range of enzyme expression levels, comparing favorably with benchmark anti-CD73 antibodies; it improved the efficacy of PD-1 blockade in vitro as well as in vivo. Our structural data indicate that a unique one-to-one Sym024-CD73 interaction engenders this comprehensive inhibition. No preclinical safety flags were observed, and the PK profile of Sym024 supported a standard clinical dosing regimen.

Conclusions: The comprehensive CD73 inhibition exhibited by Sym024 may improve the efficacy of anti-PD-(L)1/anti-CD73 combination treatment.

Purpose: Two dominant neoadjuvant radiotherapy (RT) regimens are in common use for locally advanced rectal cancer (LARC): long-course RT (LCRT; 25 × 1.8 Gy) with concomitant chemotherapy and short-course RT (SCRT; 5 × 5 Gy), typically followed by systemic chemotherapy. This study uses serial sampling to investigate the evolution of systemic and local immune responses to different RT regimens in LARC.

Experimental design: We conducted a serial sampling study involving patients receiving RT for LARC, in which longitudinal blood and tumor biospecimens were collected at baseline and at 2, 6, and 12 weeks after treatment initiation. Leukocyte concentrations via full blood count and a multiplex cytokine ELISA of plasma samples measured systemic changes. Multiplex immunofluorescence (CD8 and FOXP3) and RNA sequencing of tumor biopsies were used to assess local changes.

Results: Circulating lymphocyte concentrations tended to increase in SCRT patients and decrease in LCRT patients between week 2 and week 6 and were significantly lower in LCRT patients compared with SCRT patients at week 6 (P < 0.0001) and week 12 (P = 0.019). Additionally, we report higher densities of CD8+ and FOXP3+ tumoral lymphocytes from SCRT patients compared with LCRT patients at week 2 (CD8 P = 0.053; FOXP3 P = 0.023) and week 6 (CD8 P = 0.035; FOXP3 P = 0.0016).

Conclusions: SCRT is less lymphodepleting and induces more frequent increases in intratumoral T-cell infiltration compared with LCRT. These results are relevant to the field of radiation-immune-oncology combination studies in LARC. Furthermore, these findings may underpin early trial results, in which higher rates of response to RT-immune checkpoint inhibitor combinations have been reported with SCRT-based regimens.

Purpose: Patients with tumor mutational burden (TMB)-high tumors can derive benefit from atezolizumab, though previous studies have used inconsistent TMB cutoffs. We report data for atezolizumab in patients with TMB-high solid tumors from the phase II TAPISTRY multicohort trial, using TMB cutoffs of ≥13 and ≥16 mutations per megabase (mut/Mb).

Patients and methods: Patients with PD-L1 inhibitor-naïve, TMB-high (≥13 mut/Mb), advanced/metastatic solid tumors received atezolizumab every 21 days [1,200 mg for adults, 15 mg/kg (up to 1,200 mg/kg) for children]. The primary endpoint was independent review committee (IRC)-assessed objective response rate (ORR) for TMB ≥16 mut/Mb. Secondary endpoints (using TMB ≥13 mut/Mb) included IRC-assessed ORR, duration of response (DOR), progression-free survival (PFS), and safety.

Results: As of November 9, 2023 (median survival follow-up: 9.8 months), 148 patients received treatment. Median age was 63 years, 31.8% of patients had >2 prior therapy lines, and the most common tumor types were colorectal (29.1%), breast (8.8%), and gastroesophageal (8.8%). IRC-assessed ORR was 22.3% [95% confidence interval (CI), 15-31.2] with TMB ≥16 mut/Mb (n = 112), and 20.2% (95% CI, 13.6-28.1) with TMB ≥13 mut/Mb (n = 129). Median IRC-assessed DOR was not estimable. Median IRC-assessed PFS was 2.8 (95% CI, 1.7-5.4) and 2.7 (95% CI, 1.5-4.2) months using TMB ≥16 and ≥13 mut/Mb, respectively. Adverse events were reported in 93.2% of patients, of which 53.4% were treatment-related (no grade 5) and 40.5% were grade ≥3.

Conclusions: Atezolizumab led to moderate antitumor activity in various TMB-high solid tumors. Safety was consistent with previous reports.

Purpose: Hypopharyngeal squamous cell carcinoma (HPSCC) has a poor prognosis. Although neoadjuvant chemoimmunotherapy (nCIT) is promising, responses are heterogeneous and PD-L1 combined positive score (CPS) inadequately stratifies benefit. We sought biomarkers to guide patient selection.

Experimental design: In this prospective, single-center, single-arm phase II trial, patients with resectable locally advanced HPSCC received two cycles of neoadjuvant toripalimab, albumin-bound paclitaxel, and nedaplatin. The primary endpoint was the pathological complete response (pCR) rate. Pre-treatment tumor biopsies from a subset of patients (n=13) were analyzed by single-cell RNA sequencing (scRNA-seq) to identify determinants of response. Findings were validated in a larger cohort (n=60) using bulk RNA sequencing and immunohistochemistry.

Results: Among 70 evaluable patients, the objective response rate was 82.7%. Of the 64 patients who underwent surgery, the pCR rate was 29.7% (95% CI, 18.9%-42.7%). Baseline PD-L1 CPS was not associated with pathological response (P=0.313). Single-cell analysis revealed that the pre-treatment tumor microenvironment of responders was significantly enriched with a pro-inflammatory neutrophil subset characterized by high expression of CCL3 (Neu_CCL3). A gene signature score derived from this subset was a strong and independent predictor of pCR (AUC = 0.788), significantly outperforming PD-L1 CPS (AUC = 0.621).

Conclusions: The efficacy of nCIT in HPSCC is predetermined by a baseline immune architecture orchestrated by a CCL3+ neutrophil subset. The Neu_CCL3 gene signature is a promising, clinically translatable biomarker that can fill a critical gap in precision immunotherapy for HPSCC.

Purpose: KLK2 is an androgen-regulated gene critical in prostate cancer biology with multiple KLK2-targeted therapies in clinical development. We investigated KLK2 RNA expression patterns and associations with molecular features to provide context for emerging KLK2-targeted treatments.

Experimental design: DNA/RNA next-generation sequencing was performed on 7,078 prostate cancer specimens. KLK2-high/low RNA expression was defined as ≥75th/<25th percentiles (transcripts per million, TPM). KLK2 expression was evaluated across histologic subtypes, disease states, and metastatic sites, with correlative analyses of genomic alterations, RNA signatures, and clinical outcomes.

Results: KLK2 gene expression varied significantly by histology, with highest levels in adenocarcinoma (8.79 log2[TPM+1]) and minimal expression in histologic neuroendocrine prostate cancer (0.33 log2[TPM+1]). Expression was significantly higher in androgen deprivation therapy (ADT)/androgen receptor pathway inhibitor (ARPI)-sensitive versus ADT/ARPI-exposed tumors (8.97 vs. 8.38 log2[TPM+1], q<0.001). Localized tumors demonstrated higher expression than lymph node (8.93 vs. 8.76 log2[TPM+1]) or distant metastases (8.23 log2[TPM+1]), with visceral metastases showing the lowest levels. In the overall cohort, KLK2 expression correlated positively with androgen receptor signaling (r=0.25-0.47) and negatively with neuroendocrine signaling. High KLK2 expression was associated with significantly improved overall survival (93.9 vs. 74.4 months, hazard ratio 0.68, p<0.001) in the total cohort, with similar patterns in patients with ADT/ARPI-sensitive and ADT/ARPI-exposed disease.

Conclusions: This large-scale clinico-genomic analysis reveals distinct KLK2 expression patterns across prostate cancer histologies, tumor sites, and clinical states. These findings provide a molecular framework understanding KLK2 as a therapeutic target in prostate cancer.