Abstract LB-A31: Imprime PGG (Imprime) plus pembrolizumab (PEM): a phase 2 immunotherapeutic combination in patients selected for an Imprime-specific biomarker

Autor: Richard D. Huhn, Mable Ma, Michael Chisamore, Richard Walsh, Steven J. O'Day, Nandita Bose, Jeremy R. Graff, Steven M. Leonardo, Bruno Osterwalder, Michele Gargano, Paulette Mattson, Mark Uhlik, Radha Prathikanti, Ben J. Harrison, Jamie Lowe, Katie Ertelt, Xiaohong Qiu, Nadine Ottoson
Rok vydání: 2018
Předmět:
Zdroj: Molecular Cancer Therapeutics. 17:LB-A31
ISSN: 1538-8514
1535-7163
DOI: 10.1158/1535-7163.targ-17-lb-a31
Popis: Imprime PGG (Imprime) is a novel immunotherapeutic that acts as a non-self danger signal to activate the innate immune system and coordinate an adaptive immune system response. In multiple preclinical tumor models, Imprime significantly enhances anti-tumor efficacy of multiple immune checkpoint inhibitors (CPI). Mechanistically, Imprime directly binds to innate immune effector cells via the formation of an immune complex with naturally-occurring anti-β glucan antibodies (ABA). This immune complex is required for Imprime to activate innate effector functions, e.g. monocyte and dendritic cell activation, and enhanced cytokine production. In a recently completed healthy volunteer study, activation of innate immune cell functions was demonstrated after intravenous (IV) infusion of Imprime in subjects with pre-treatment [Tx] ABA levels >20 µg/ml. In ex vivo human donor blood studies, whole blood from subjects with low (e.g., insufficient) ABA failed to show innate immune activation unless rescued by the addition of purified ABA (ABA from the serum of high ABA donors) or commercial immune globulin. Retrospective analyses of data from previous clinical trials showed that higher pre-Tx ABA levels correlated with enhanced overall survival in patients (pts) treated with Imprime. Collectively, these data support the hypothesis that ABA are essential to the therapeutic benefit of Imprime. A phase 2 clinical trial combining Imprime (4 mg/kg weekly IV) with PEM (200 mg, q3w) has begun in metastatic melanoma pts who have failed a CPI and in CPI naïve-triple negative breast cancer (TNBC) pts who have failed chemotherapy. Pts are screened for sufficient ABA (>20 μg/ml) by ELISA. Pre- and on- Tx biopsies at 6 wks and at time of response/progression or end of Tx are requested to assess immune cells at the tumor site by multi-channel immunofluorescence. Blood samples are collected pre- and post- Imprime infusion on Day 1 of each treatment cycle for the first 6 cycles and q4 cycle thereafter. The first TNBC pt had a pre-Tx ABA of 31 µg/ml. Following 6 wks of Tx, the pt’s total target lesion mass was reduced >40%. Partial response continued at 12, 18 and 24 wks (>50% reduction vs baseline). A biopsy of a remaining pelvic lesion after 18 wks Tx revealed primarily fibrotic tissue. Blood samples showed evidence of innate immune activation including increased expression of MCP-1, IL-8, chemokines targeting CCR5 and CXCR3 that are associated with enhanced T cell infiltration and effector function. The first melanoma pt (pre-Tx ABA 42 µg/ml) showed a modest increase in lesion size at 12 wks (+12% versus baseline). Pre- and on-Tx (6 wk) biopsy material (from two different lesion locations) was obtained for multichannel immunofluorescence. The pre-Tx biopsy tumor sample was primarily devoid of immune cells. In contrast, the on-Tx biopsy tumor sample indicates extensive infiltration of the tumor bed by CD8 and CD4 T cells, and innate immune cells. Previous Imprime clinical and ex vivo data suggest that sufficient ABA may be important for Imprime-mediated innate immune activation. Early clinical observations in ABA pre-selected patients support the notion that Imprime may provide benefit in combination with PEM in these two populations. Citation Format: Steven O'Day, Nandita Bose, Mark Uhlik, Radha Prathikanti, Ben Harrison, Steven Leonardo, Richard Huhn, Nadine Ottoson, Xiaohong Qiu, Richard Walsh, Paulette Mattson, Mable Ma, Katie Ertelt, Jamie Lowe, Michele A. Gargano, Michael Chisamore, Bruno Osterwalder, Jeremy Graff. Imprime PGG (Imprime) plus pembrolizumab (PEM): a phase 2 immunotherapeutic combination in patients selected for an Imprime-specific biomarker [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr LB-A31.
Databáze: OpenAIRE
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