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Publication Date
11-2018
Keywords
Cancer, tumor microenvironment, cancer immunity, immunotherapy, clinical trial
Disciplines
Oncology
Abstract
Background: Agonist CD40 mAbs can mediate antitumor immunity through multiple mechanisms, including enhancing tumor antigen presentation, activation of tumoricidal macrophages, and direct growth inhibition/killing of CD40- expressing tumor cells. To fully exploit these mechanisms may require the mAb to be dosed at levels that provide significant tumor and tissue penetration, without dose-limiting-toxicities (DLT) from systemic CD40 activation. Our agonist CD40 mAb, CDX-1140, was selected based on its unique and linear dose-dependent in vitro and in vivo activity and is postulated will achieve maximum agonist activity at dose levels associated with good systemic exposure. CDX-1140 is a fully human IgG2 agonist anti-CD40 mAb that activates dendritic cells (DCs) and B cells in an Fc receptor independent manner and has potent antitumor activity against CD40-expressing cancer cells. In addition, CDX-1140 does not block the natural CD40-CD40L interaction; combination of CDX-1140 with added soluble CD40L is synergistic in the activation of immune cells suggesting a potential to enhance in vivo CD40L dependent immune responses. In toxicology studies, CDX-1140 demonstrated potent CD40-mediated pharmacological effects without significant toxicities.
Methods: A phase 1 dose-escalation study of CDX-1140 (CDX1140-01; NCT03329950) is underway in patients with advanced tumors who have exhausted standard-of-care treatment options. The primary endpoint is determining the safety profile and maximum tolerated dose. Secondary endpoints include pharmacokinetics, immunogenicity, clinical and biological outcome assessments. Baseline and on-study biopsies will be used to explore the pharmacodynamic effects of CDX-1140 in the tumor microenvironment (TME). The dose escalation (DE) portion evaluates CDX-1140, given every 4 weeks, at doses from 0.01 to 3 mg/kg; the first 2 cohorts are single-patient cohorts and all subsequent DE cohorts are conducted utilizing a 3+3 design. Tumor-specific expansion cohorts will further explore the activity of CDX-1140. This study will also evaluate CDX-1140 in combination with CDX-301 (rhFLT3L), a DC growth factor that markedly increases DC numbers, including the CD141+ subset which are critical to an antitumor immune response and are often scarce within the TME.
Results: To date, CDX-1140 cohorts at 0.01 (n=2), 0.03 (n=1), and 0.09 (n=3) mg/kg have been completed without any drug-related serious adverse events, infusion reactions, or DLTs reported. The only drug related toxicity has been grade 1 fatigue (n=2) . Expected pharmacodynamic effects, including transient, dose-dependent decreases in lymphocyte counts and dose-dependent increases in serum IL-12p40 and TNF-Alpha, have been observed.
Conclusions: The early data suggest that CDX-1140 has the expected immune activating and safety profile.
Ethics Approval: The study was approved by University of Pennsylvania, approval number 828733; Mount Sinai School of Medicine, approval number IRB-18-00213; Providence Health and Services, approval number 201700532 and Western Institutional Review Board, approval number 115925
Clinical Institute
Cancer
Specialty/Research Institute
Oncology
Specialty/Research Institute
Earle A. Chiles Research Institute
Comments
Poster presented at Society for Immunotherapy of Cancer Annual Meeting, Washington, D.C., November 7 – 11, 2018.