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

Abstract

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).

Keywords: Cytokine release syndrome; Dose escalation study; Human leukocyte antigen-G; JNJ-78306358; Phase 1; Solid tumors.

Fig. 1

Dose escalation. Step-up doses and the treatment dose are shown for each cohort. DLT dose-limiting toxicities, MABEL minimum anticipated biological effect level, SC subcutaneous

Fig. 2

Response and time-on-treatment arranged by cohort; all treated analysis set. AE adverse events, d/c discontinuation, PD progressive disease, SD stable disease

Fig. 3

Mean serum concentration–time profiles of JNJ-78306358 after first treatment dose administration. Conc. Concentration, Q1W once every week, SC subcutaneous, SU step-up

Fig. 4

Cytokine induction following administration of JNJ-78306358: a Maximum fold change after treatment dose compared to baseline arranged by cohorts b Maximum fold change after treatment dose compared to baseline arranged by CRS grade c Comparison of IL-6 to IL-10 ratio arranged by CRS grade. a Box plot of maximum fold change (FCHG) of serum IFNγ, IL-6 and IL-10 across cohorts. Maximum fold change, shown in log10 scale, is defined as the highest fold change between post-treatment and baseline values across all sample collection timepoints. b Box plot of maximum fold change of serum IFNγ, IL-6 and IL-10 by CRS grade. No CRS is represented by grade 0. Maximum fold change, shown in log10 scale, is defined as the highest fold change between post-treatment and baseline values across all sample collection timepoints. c Box plot of maximum IL-6 to IL-10 ratio by CRS grade. Maximum ratio is defined as the highest ratio between IL-6 and IL-10 values across all sample collection timepoints. CRS cytokine release syndrome, FCHG fold change, IL interleukin

Fig. 5

Effect of JNJ-78306358 on peripheral T cell migration, activation, and proliferation: a Induction of CD8 + T cell (CD8 + /CD3 +) margination by JNJ-78306358: Representative cohort of 15–48-180 ug b JNJ-78306358 induced activation of cytotoxic T cells (CD38 + /CD8 + and HLA-DR + /CD8 +) c T cell proliferation (Ki67 + /CD3 +) was induced by JNJ-78306358. a Longitudinal tracking of fold change (FCHG) of peripheral CD8 + /CD3 + T cell count compared to baseline levels in the 15–48-180 ug cohort. Fold change is presented in log10 scale. b Box plot of maximum fold change of CD38 + /CD8 + and HLA-DR + /CD8 + MdFI cohorts. Maximum fold change, shown in log10 scale, is defined as the highest fold change between post-treatment and baseline values across all sample collection timepoints. c Box plot of maximum fold change of the percentage of Ki67/CD3 + by treatment cohorts. Maximum fold change, shown in log10 scale, is defined as the highest fold change between post-treatment and baseline values across all sample collection timepoints. CD cluster of differentiation, CRS cytokine release syndrome, EOT end of treatment, FCHG fold change, HLA-DR human leukocyte antigen-DR isotype, MdFI median fluorescent intensity, SC subcutaneous

Fig. 6

a Summary of HLA-G positivity (H-score > 0) by IHC in archival tissues b Representative HLA-G IHC images. *H-score > 0 a HLA-G levels in archival tumors was assessed by an IHC assay using 4H84 mAb. Global H-score from all IHC evaluable tumors is shown and separated by tumor types. Asterisk indicates samples with global H-score above 0. b Representative IHC images of HLA-G expression in archival tissues detected by the 4H84 mAb. CRC colorectal cancer, HLA-G human leukocyte antigen-G, IHC immunohistochemistry, RCC renal cell carcinoma