Safety and clinical activity of JNJ-78306358, a human leukocyte antigen-G (HLA-G) x CD3 bispecific antibody, for the treatment of advanced stage solid tumors

Background JNJ-78306358 is a bispecific antibody that redirects T cells to kill human leukocyte antigen-G (HLA-G)-expressing tumor cells. This dose escalation study evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of JNJ-78306358 in patients with advanced...

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Vydáno v:Cancer Immunology, Immunotherapy : CII Ročník 73; číslo 10; s. 205
Hlavní autoři: Geva, Ravit, Vieito, Maria, Ramon, Jorge, Perets, Ruth, Pedregal, Manuel, Corral, Elena, Doger, Bernard, Calvo, Emiliano, Bardina, Jorge, Garralda, Elena, Brown, Regina J., Greger, James G., Wu, Shujian, Steinbach, Douglas, Yao, Tsun-Wen Sheena, Cao, Yu, Lauring, Josh, Chaudhary, Ruchi, Patel, Jaymala, Patel, Bharvin, Moreno, Victor
Médium: Journal Article
Jazyk:angličtina
Vydáno: Berlin/Heidelberg Springer Berlin Heidelberg 06.08.2024
Springer Nature B.V
Témata:
Adult
Aged
Aged, 80 and over
Antibodies, Bispecific - administration & dosage
Antibodies, Bispecific - adverse effects
Antibodies, Bispecific - pharmacology
Antibodies, Bispecific - therapeutic use
Antigens
Antitumor activity
Bispecific antibodies
Cancer Research
CD3 antigen
CD3 Complex - immunology
Cell activation
Colorectal cancer
Colorectal carcinoma
Cytokines
Dosage
Female
Histocompatibility antigen HLA
HLA-G Antigens
Humans
Immunohistochemistry
Immunology
Kidney cancer
Leukocytes
Lymphocytes T
Male
Medicine
Medicine & Public Health
Metastases
Middle Aged
Monoclonal antibodies
NCT
NCT04991740
Neoplasm Staging
Neoplasms - drug therapy
Neoplasms - immunology
Oncology
Ovarian cancer
Ovarian carcinoma
Patients
Pharmacodynamics
Pharmacokinetics
Pneumonitis
Renal cell carcinoma
Solid tumors
Tumor cells
Tumors
Dose escalation study
JNJ-78306358
Cytokine release syndrome
Phase 1
Solid tumors
Human leukocyte antigen-G
ISSN:1432-0851, 0340-7004, 1432-0851
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Shrnutí:Background JNJ-78306358 is a bispecific antibody that redirects T cells to kill human leukocyte antigen-G (HLA-G)-expressing tumor cells. This dose escalation study evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of JNJ-78306358 in patients with advanced solid tumors. Methods Adult patients with metastatic/unresectable solid tumors with high prevalence of HLA-G expression were enrolled. Dose escalation was initiated with once-weekly subcutaneous administration with step-up dosing to mitigate cytokine release syndrome (CRS). Results Overall, 39 heavily pretreated patients (colorectal cancer: n = 23, ovarian cancer: n = 10, and renal cell carcinoma: n = 6) were dosed in 7 cohorts. Most patients (94.9%) experienced ≥ 1 treatment-emergent adverse events (TEAEs); 87.2% had ≥ 1 related TEAEs. About half of the patients (48.7%) experienced CRS, which were grade 1/2. Nine patients (23.1%) received tocilizumab for CRS. No grade 3 CRS was observed. Dose-limiting toxicities (DLTs) of increased transaminases, pneumonitis and recurrent CRS requiring a dose reduction were reported in 4 patients, coinciding with CRS. No treatment-related deaths reported. No objective responses were noted, but 2 patients had stable disease > 40 weeks. JNJ-78306358 stimulated peripheral T cell activation and cytokine release. Anti-drug antibodies were observed in 45% of evaluable patients with impact on exposure. Approximately half of archival tumor samples (48%) had expression of HLA-G by immunohistochemistry. Conclusion JNJ-78306358 showed pharmacodynamic effects with induction of cytokines and T cell activation. JNJ-78306358 was associated with CRS-related toxicities including increased transaminases and pneumonitis which limited its dose escalation to potentially efficacious levels. Trial registration number ClinicalTrials.gov (No. NCT04991740).
Bibliografie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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ISSN:1432-0851
0340-7004
1432-0851
DOI:10.1007/s00262-024-03790-7