Journal for Immunotherapy of Cancer最新文献

Background: M6223 is an intravenous (IV), Fc-competent, fully human, antagonistic, anti-T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) antibody. Bintrafusp alfa (BA) is a bifunctional fusion protein that simultaneously blocks nonredundant immunosuppressive TGF-β and PD-(L)1 pathways.

Methods: This first-in-human, dose-escalation study in patients with advanced solid tumors (N=58; aged ≥18 years, ECOG PS≤1) evaluated M6223 alone (Part 1A, n=40; M6223 10-2400 mg every 2 weeks, n=32; M6223 2400 mg every 3 weeks, n=8) or with BA (Part 1B, n=18; M6223 300-1600 mg with BA 1200 mg; both every 2 weeks, intravenous). Primary objectives were safety, tolerability, maximum tolerated dose (MTD) and recommended dose for expansion (RDE). Additional objectives included pharmacokinetics, pharmacodynamics and clinical activity (NCT04457778).

Results: Two dose-limiting toxicities were observed: grade 3 adrenal insufficiency (Part 1A: M6223 900 mg every 2 weeks) and grade 3 anemia (Part 1B: M6223 300 mg, only BA related). MTD was not reached. Overall, median overall survival and progression-free survival were 7.6 (95% CI 4.9, 12.0) and 1.4 (95% CI 1.3, 1.8) months, respectively. Stable disease as best response was observed in 13 (32.5%) and 5 (27.8%) patients in parts 1A and 1B, respectively. M6223±BA displayed a linear pharmacokinetic profile. Anti-TIGIT mode-of-action-related pharmacodynamic effects were observed in peripheral blood and in tumor tissue. RDEs were 1600 mg every 2 weeks or 2400 mg every 3 weeks for M6223 monotherapy and 1600+1200 mg every 2 weeks for M6223+BA.

Conclusions: M6223±BA had a manageable safety profile, with RDEs defined for both monotherapy and combination therapy. Further evaluation of M6223 is ongoing in combination with the PD-L1 inhibitor avelumab in patients with advanced urothelial carcinoma (JAVELIN Bladder Medley; NCT05327530).

Trial registration number: NCT04457778.

Background: Immune checkpoint inhibitors (ICIs) are the gold standard therapy in patients with deficient mismatch repair (dMMR)/microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC). A significant proportion of patients show resistance, making the identification of determinants of response crucial. Growing evidence supports the role of sex in determining susceptibility to anticancer therapies, but data is lacking for patients with MSI-H CRC.

Methods: In this real-world cohort comprising 624 patients with MSI-H mCRC receiving ICIs, we investigated the impact of sex on patients' outcomes, overall and according to RAS-BRAF mutational status or type of treatment (anti-PD-(L)1 with or without anti-CTLA-4 agents). We then investigated these associations also in two independent cohorts of patients with early-stage or advanced MSI-H CRC unexposed to ICIs. Finally, we explored two public microarray and RNA-seq datasets from patients with non-metastatic or metastatic MSI-H CRC to gain translational insights on the association between sex, BRAF status and immune contextures/ICI efficacy.

Results: Although no differences were observed between females and males either overall or in the BRAF wild-type cohort, male sex was associated with inferior progression-free survival (PFS) and overall survival (OS) in the BRAF mutated cohort (in multivariable models, HR for PFS: 1.79, 95% CI: 1.13 to 2.83, p=0.014, and for OS: 2.33, 95% CI: 1.36 to 3.98, p=0.002). Males receiving anti-PD-(L)1 monotherapy had the worst outcomes, with a 3-year PFS and 3-year OS of 23.9% and 41.8%, respectively, while the addition of anti-CTLA-4 agents rescued such a worse outcome. We also observed that females experienced a higher frequency of any-grade immune-related adverse events. Conversely, sex was not prognostic in the independent cohorts of patients with MSI-H CRCs not treated with ICIs. Exploratory transcriptomic analyses suggest that tumors of males with BRAF mutated MSI-H metastatic CRC are characterized by an enrichment of androgen receptor signature and an immune-depleted microenvironment, with a reduction in memory B cells, activated natural killer cells, and activated myeloid dendritic cells.

Conclusions: Overall, our findings suggest a complex interplay between sex and BRAF mutational status that may modulate the activity of ICIs in patients with MSI-H mCRC and pave the way to novel tailored strategies.

Background: Natural Killer (NK) cells have intrinsic anticancer activity that can be redirected toward acute myeloid leukemia (AML) with chimeric antigen receptor (CAR) engineering. Here, we study the functional consequences of CAR binding affinity and targeted epitope on CAR-NK cell activation, cytolytic synapse formation, and antitumor activity.

Methods: We characterized NK-92 and primary NK cell populations expressing variant affinity AML-specific CARs containing single-chain variable fragments (scFvs, 26292 or 7G3) targeting two epitopes on CD123. 26292 affinity variants were discovered through directed evolution of an error-prone mutagenic library, while 7G3 affinity variants were previously reported. The resulting CAR-NK cell panel was studied with in vitro binding, activation, and cytotoxicity studies and in mouse xenograft models.

Results: 26292 and 7G3 CARs of variable CD123 binding affinities were highly expressed in NK cells and conferred antigen-specific activation in vitro. High-resolution imaging demonstrated greater clustering of high-affinity 7G3 CAR-NK cells and consequent AML target cell death in a short-term time lapse. Low-affinity 7G3 CAR-NK cells exhibited enhanced antigen density discrimination with greater membrane-proximal signaling, cytokine production, and cytotoxicity. In longer-term assays, low-affinity 7G3 CAR-NK cells demonstrated more sustained killing of AML cells. In vivo testing highlighted greater expansion of low-affinity 7G3 CAR-NK cells in two xenograft models.

Conclusions: Expression of 26292 and 7G3 CARs with a range of CD123 binding affinities in NK cells leads to antigen-specific activation and cytotoxicity against AML. Affinity-based differences in functional activation and antitumor activity are dependent on time course and are scFv/epitope specific.

Background: Advanced triple-negative breast cancer (TNBC) is prone to brain metastasis (BrM). The precise molecular mechanism responsible for this phenomenon has not yet been completely established, so it is vital to comprehend the molecular mechanism behind it.

Methods: The protein chip analysis was conducted to identify any abnormal UBE2T protein expression in TNBC, especially BrM. Here, we used public databases and bioinformatics analysis as well as clinical samples from different cohorts to investigate the interrelationship between UBE2T/CDC42/CD276. This predicted relationship was then repeatedly validated using different in vivo and in vitro experimental methods. Additionally, multiple experimental approaches were implemented, encompassing western blotting, Co-IP, GST pull-down, flow cytometry, mass spectrometry, immunofluorescence, immunohistochemistry, and qRT-PCR to reveal the molecular mechanism of UBE2T-mediated immune escape and BrM.

Results: Our results indicate that expressed at elevated levels in breast cancer, UBE2T is negatively linked to patient prognosis, especially in BrM of TNBC. Data from clinical samples from our different cohorts and TCGA indicate a significant correlation between UBE2T and immunosuppression. Mechanistically, UBE2T directly interacts with CDC42, promoting its K48-linked polyubiquitination and proteasomal degradation, thereby inhibiting CDC42 from degrading CD276 via the autophagy-lysosomal pathway, indirectly upregulating CD276 and thereby impairing the CD8⁺ T cells function, ultimately mediating tumor immune escape and BrM. Finally, animal experimental results also showed that inhibition of UBE2T elevated the TNBC sensitivity to immune checkpoint CD276 blockade and inhibited BrM of TNBC.

Conclusions: In conclusion, our results indicate a new mechanism whereby UBE2T-mediated ubiquitination positively controls the UBE2T/CDC42/CD276 axis to upregulate tumor cell expression of CD276 and thereby impair CD8⁺ T cells function, ultimately leading to tumor cell immune escape and BrM.

Background: Clofarabine (Clo) is a Food and Drug Administration (FDA)-approved drug for the treatment of acute lymphoblastic leukemia; however, its effects on solid tumors remain largely unknown.

Methods: In vitro and in vivo experiments have demonstrated the cytotoxic effects of Clo on melanoma and lung cancer. The molecular mechanisms of Clo-induced tumor cell death were analyzed using western blotting, ELISA, reverse transcription-PCR, immunofluorescence, co-immunoprecipitation (CO-IP), short hairpin RNA, co-culture, chromatin immunoprecipitation, and flow cytometry. Clinical data sets were used to analyze the correlation between stimulator of interferon genes (STING)-NFκB signaling and immune infiltration.

Results: In this study, Clo significantly reduced the growth of melanoma and lung cancer cells. Furthermore, Clo treatment induced GSDME-mediated pyroptosis. Most importantly, Clo administration dramatically increased the cytotoxic activity of CD8⁺ T cells in vitro and in vivo. Mechanistically, the administration of Clo induced the interaction of P53 with STING, which activated the non-canonical STING-NFκB pathway; consequently, NF-κB directly bound to the promoter regions of its target genes, including CCL5, CXCL10, HLAs and BAX. This resulted in apoptosis, pyroptosis, and immunogenic cell death in tumor cells by Clo. Furthermore, Clo-induced GSDME-mediated pyroptosis partly assists in activating T cell immunity via CCL5 and CXCL10. The non-canonical STING-NF-κB pathway is the crucial signaling pathway that initiates and links apoptosis, pyroptosis, and immunogenic cell death.

Conclusions: Our study is the first to show that Clo, an FDA-approved drug, induces tumor cell apoptosis, GSDME-related pyroptosis, and CD8⁺ T-cell antitumor activity via the non-canonical P53-STING-NF-κB signaling pathway, providing a novel strategy for the clinical therapy of melanoma and lung cancer.

Introduction: Adoptive cell therapy using tumor-infiltrating lymphocytes (TILs) has proved to be an effective treatment for metastatic melanoma, even in patients failing anti-PD-1 blockade. Nevertheless, progression is observed in a substantial subgroup of patients following an initial objective response to treatment with TILs. These patients might benefit from additional consolidating treatment before clinical progression, but thus far, it is not possible to identify this subgroup of patients prone to progress. In this study the predictive value of early metabolic response after TIL therapy is explored.Materials and methods: 60 patients treated with TIL therapy in 4 different clinical trials and with available [18F]2-fluoro-2-deoxy-d-glucose positron emission tomography-CT (FDG-PET/CT) scans at baseline and at least one follow-up scan 6-8 weeks and/or 12-16 weeks post-TIL infusion were included.Results: Obtaining complete metabolic response (CMR) was associated with significantly superior median overall survival (mOS) compared with not obtaining CMR (p<0.0001). Of particular interest, metabolic response divided RECIST partial responders (22 patients) into two groups with significantly different clinical outcomes. Neither mOS (range 32.2-149.8+) nor median progression-free survival (mPFS; range 20.7-123.4+) were reached for patients with partial response (PR)/CMR (10 patients), whereas patients with PR/non-CMR (12 patients) had a mOS of 28.7 months (p=0.0016) and a mPFS of 7.8 months (p<0.0001).Overall, not achieving a CMR was associated with a short mPFS of 3.2 months, and 97.9% (47/48) of all patients in this group progressed within 12 months.Conclusion: In conclusion, early CMR is a strong predictor of long-term survival after TIL therapy in metastatic melanoma patients. Furthermore, FDG-PET/CT scans appear superior to CT scans for providing early prognostic information after TIL therapy in melanoma and can be used to tailor patient-specific management and follow-up strategies.

Background: OH2 is an oncolytic virus derived from herpes simplex virus type 2. A phase Ia/Ib clinical trial in China was conducted in patients with unresected stage III-IV melanoma, the majority of whom had the acral type, to assess the safety and preliminary efficacy of OH2.

Methods: The trial enrolled patients with histologically confirmed unresectable stage III or advanced stage IV melanoma. In phase Ia, nine patients received OH2 single-dose treatment across three dose levels (10⁶, 10⁷, and 10⁸ CCID₅₀/mL, where CCID₅₀ represents cell culture infectious dose 50%) while six patients underwent multidose therapy. Phase Ib expanded the proposed dose. Antitumor efficacy was evaluated using the Response Evaluation Criteria in Solid Tumors and immune-RECIST guidelines. NCT04386967 is the clinical trial identifier.

Results: All 44 patients were enrolled. OH2 was well tolerated without serious adverse events (AEs) or deaths reported. No Grade 3 or higher treatment-related AEs occurred. In phase Ia, the 1-year survival rate was 92.9% (95% CI, 59.1% to 99.0%), with a median overall survival of 28.9 months (95% CI, 12.7 to not reached). In phase Ib, 10 patients achieved immune-partial response (iPR)/partial response (PR), yielding an objective response rate (ORR) of 37.0% (95% CI, 19.4% to 57.6%), with 6 patients still responding. The rate of the durable response (PR or complete response lasting at least 6 months) was at least 29.6% (8/27). Notably, 7 of 12 III-IVM1a patients who previously received programmed cell death protein-1 (PD-1) therapy achieved iPR/PR, with an ORR of 58.3% (95% CI, 27.7% to 84.8%) and a disease control rate of 75.0% (95% CI, 42.8% to 94.5%). Biomarker analysis indicated that elevated baseline neutrophil activation state correlated with poorer clinical outcomes. A phase III clinical trial is ongoing in China (NCT05868707).

Conclusions: OH2 oncolytic virotherapy exhibited a favorable safety profile without dose-limiting toxicities (DLTs) and demonstrated durable antitumor efficacy in patients with melanoma, especially in those who had progressed on anti-PD-1 treatment.

Trial registration number: ClinicalTrials.gov identifier NCT04386967.

Background: CD4⁺ T-cell lymphocytopenia and immune dysfunction are factors that drive the onset and persistence of Kaposi sarcoma (KS) in people with (PWH) and without HIV. Standard chemotherapy agents for KS can contribute to increasing CD4⁺ T cell lymphocytopenia. IL-7 is a cytokine that is essential in T-cell development, proliferation and homeostasis. In PWH, IL-7 administration leads to increased numbers of circulating central memory and naïve T-cell phenotypes.

Methods: In this multicenter phase I study with a 3+3 dose escalation design, participants with KS with or without HIV received up to four intramuscular injections of IL-7 (NT-I7) every 9 weeks. The primary endpoint of the study was to evaluate safety over three escalating dose levels (DL) of NT-I7 (DL1:480 µg/kg, DL2: 960 µg/kg and DL3: 1200 µg/kg) and identify a maximum tolerated dose. Secondary endpoints included evaluation of antitumor activity per the modified AIDS Clinical Trials Group Criteria and assessment of the effect of NT-I7 on the kinetics of CD4⁺ and CD8⁺ T-cells.

Results: Eight cisgender male participants (five with HIV infection) were enrolled. Six participants were treated at DL1, and two were treated at DL2. The study was closed to accrual after enrolment of the second participant on DL2 due to termination of study funding. Four of the eight participants (three in DL1 and one in DL2) completed all four doses of the NT-I7. With regard to treatment-emergent adverse events (AEs), all participants had + and CD8⁺ T-cell counts increased among all participants following administration of NT-I7. Participants who experienced a response had HIV and lower CD4/CD8 ratio at baseline and throughout the study as compared with those who did not have KS response to NT-I7.

Conclusions: Preliminary data demonstrate safety and activity of IL-7 in patients with KS and activity specifically among individuals HIV-associated KS.

Trial registration number: NCT04893018.