Clinical Cancer Research最新文献

Purpose: Adenosine signaling may be a central immune suppressive mechanism in several cancers, and blockade of the rate-limiting CD73 AMP-to-adenosine enzyme has been demonstrated to improve clinical efficacy of 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. Here, 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 intra-tumoral enzymatic inhibition and immune cell recruitment were assessed. We investigated Sym024-CD73 interaction using surface plasmon resonance, cryo-electron microscopy, site-directed mutagenesis, and population level complex formation through size-exclusion-chromatography with light scatter mass detection. Preclinical safety and pharmacokinetics were assessed in monkeys.

Results: Sym024 effectively blocked CD73 across a large range of enzyme expression levels, comparing favorably to 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 pre-clinical safety flags were observed, and the pharmacokinetics 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: 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/megabase (mut/Mb).

Methods: Patients with PD-L1 inhibitor-naïve,TMB-high (≥13 mut/Mb) advanced/metastatic solid tumors received atezolizumab every 21 days (1200 mg adults, 15 mg/kg [up to 1200 mg/kg] children).

Primary endpoint: 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% CI, 15.0-31.2) 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 (AEs) were reported in 93.2% of patients, of which 53.4% were treatment-related (no grade 5) and 40.5% were grade ≥3.

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

Clinical trial number: NCT04589845.

Purpose: Two dominant neoadjuvant radiotherapy (RT) regimens are in common use for locally advanced rectal cancer (LARC): long-course radiotherapy (LCRT;25x1.8Gy) with concomitant chemotherapy and short-course radiotherapy (SCRT;5x5Gy) typically followed by systemic chemotherapy. This study uses serial sampling to investigate the evolution of systemic and local immune responses to different radiotherapy regimens in LARC.

Experimental design: We conducted a serial sampling study involving patients receiving radiotherapy 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 to 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 to 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 lympho-depleting and induces more frequent increases in intra-tumoral T cell infiltration compared to LCRT. These results are relevant to the field of radiation-immune-oncology combination studies in LARC. Furthermore, these findings may underpin early trial results, where higher rates of response to radiotherapy-immune checkpoint inhibitor combinations have been reported with SCRT-based regimens.