Phase 1 study of IMCnyeso, a T cell receptor bispecific ImmTAC targeting NY-ESO-1-expressing malignancies

Abstract

IMCnyeso, an immune mobilizing monoclonal T cell receptor against cancer (ImmTAC) bispecific (New York esophageal squamous cell carcinoma [NY-ESO]×CD3) T cell engager, targets an NY-ESO-1/L-antigen family member-1 isoform A (LAGE-1A) peptide presented by histocompatibility leukocyte antigen (HLA)-A∗02:01. In this phase 1 study, 28 HLA-A∗02:01+ patients with advanced NY-ESO-1/LAGE-1A-positive advanced tumors (n = 28) receive IMCnyeso weekly intravenously (dose range: 3-300 μg; 7 dose-escalation cohorts). The primary objective is to identify the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D); additional objectives include preliminary anti-tumor activity, pharmacokinetics, immunogenicity, and pharmacodynamic changes. The study was terminated before fully enrolling dose escalation, and the MTD was not identified. There are no treatment-related discontinuations or deaths. The most common adverse events are grade 1/2 cytokine release syndrome and associated symptoms. Cytokine induction and transient lymphocyte count decreases are observed at doses 30-300 μg. At these doses, preliminary efficacy includes mixed response (2 patients) and a median overall survival of 12 months. IMCnyeso is well tolerated and, at doses ≥30 μg, induces pharmacodynamic changes consistent with T cell redirection. This study was registered at ClinicalTrials.gov (NCT03515551).

Keywords: ImmTAC; NY-ESO; T cell receptor; bispecific; cancer-testis antigen; dose escalation; immunotherapy; solid tumors; synovial sarcoma.

Graphical abstract

Figure 1

Disposition of participants (Consort diagram)

Figure 2

Incidence and severity of pyrexia Incidence and severity of pyrexia as a function of dose level, following the first 4 doses of IMCnyeso.

Figure 3

Pharmacokinetics IMCnyeso serum concentration (mean + SD for each cohort) versus time profiles following the first 4 weekly IV doses. See Table S1 for the number of participants in each cohort.

Figure 4

Pharmacodynamic changes with IMCnyeso (A) Induction of IFNγ, IL-2, IL-6, IL-8, IL-10, and TNF-α following the first dose of IMCnyeso, as a function of dose (n = 9, 14, and 3 at <30, 30, and 100 μg, respectively). Median and inter-quartile range (IQR) shown. (B) IL-6 induction as a function of dose level, following the first 4 doses of IMCnyeso. Median and interquartile range are shown. (C) Reduction in absolute lymphocyte counts following the first and second doses of IMCnyeso, as a function of dose. (D) Percent change in absolute lymphocyte count (ALC) and absolute neutrophil count (ANC) at 24 h and 7 days post second dose for patients receiving <30 (n = 7), 30 (n = 5), and 100 μg (n = 14) at dose 2. Median and IQR shown.

Figure 5

Efficacy outcomes (A) Change in sum of target lesion diameters for evaluable patients with synovial sarcoma who had (n = 7) or had not (n = 11) received prior TCR-T therapy by dose group (gray: <30 μg, blue: 30 μg, green: 100 μg, orange: >100 μg). Two response-evaluable patients are not shown; one had non-target lesions only (Best overall response [BOR] of stable disease) and one missed pre-treatment scans (BOR progressive disease). (B) Baseline and on-treatment scans for a patient (30 μg cohort) with mixed response (reduction in the lesion marked in yellow but increase in the lesions marked in red). (C) Kaplan-Meier plot of overall survival for patients who received <30 μg IMCnyeso versus those who received ≥30 μg IMCnyeso.