Abstract Immune checkpoint inhibitors (ICI) have shown limited response in breast cancers, especially the hormone receptor (HR) positive/human epidermal growth factor receptor 2-negative (Her2-) subtype that is considered to be ‘immunologically cold’ in comparison to the TNBC and Her2+ subtypes. Results from Keynote-028 study showed a ORR of 12% to anti-PD1 antibody, pembrolizumab (KEYTRUDA®; PEM) in previously treated HR+/HER2-/programmed death ligand 1-positive (PD-L1-positive) advanced breast cancer patients. With limited options available for these patients, there is a significant unmet need to expand the clinical benefit from ICI to increased numbers of patients. Imprime PGG (Imprime) is a novel beta glucan acting as a pathogen-associated molecular pattern (PAMP) that drives a cascade of immune activating events. Imprime treatment repolarizes the immunosuppressive microenvironment, activates the maturation of antigen presenting cells, and has significantly enhanced the efficacy of ICI therapy in several preclinical tumor models. Imprime has been studied in combination with PEM, in metastatic TNBC and advanced melanoma in a recently completed Ph2 trial (IMPRIME 1) where in TNBC pts the objective response rate (ORR) = 15.9%, disease control rate (DCR) = 54.5%, median duration of response (mDoR)=12.7mo, median progression free survival (mPFS) =2.86 mo, 12-month overall survival (OS) rate = 57.6%, and median OS= 16.4 months. Clinical benefit in IMPRIME 1 was particularly evident in a subset of pts, mTNBC “converters” (12/44 total TNBC pts) who had originally been diagnosed with ER/PR+ disease and progressed through endocrine therapies +/- CDK4/6 inhibitors. In these 12 TNBC converters, the ORR = 50%, DCR = 83%, mDoR=11.2, mPFS=5.6 mo, 12-month OS rate=64.8%, and mOS= 17.4 months. Imprime is now being explored in pts with hormone-resistant metastatic breast cancer (MBC) in combination with PEM. This is a phase 2, Simon’s 2-Stage study of pts with MBC who have progressed through prior hormonal therapy with at least one CDK4/6 inhibitor. All pts will receive Imprime 4 mg/kg/wk + PEM 200 mg Q3wk. A total of 23 pts will be enrolled into Stage 1. If ≥4 pts in Stage 1 have an objective response after 12 wks of treatment, the study will proceed into Stage 2. Twenty-four (24) pts will be enrolled in Stage 2 for a total combined population of 47 pts. Rejection of the null hypothesis will require documenting at least 10 objective responses in the total population. Main eligibility criteria include a diagnosis of MBC having failed prior hormonal therapy with at least one CDK4/6 inhibitor, ≤1 prior line of chemotherapy, serum ABA level of ≥20 µg/mL, and no prior ICI exposure. The primary endpoint is ORR (per RECIST v1.1); secondary endpoints are mPFS, PFS, mOS, OS, DCR, DoR, and safety. Exploratory objectives will assess the impact of the treatment combination on immune activating events in peripheral blood and at the tumor level, and correlate changes in PD-L1 status, the tumor microenvironment, and serum ABA with response. Point estimates with the exact 95% confidence intervals of ORR and DCR will be computed. For mPFS, PFS, mOS, OS, and DoR, medians, first, and third quartiles with 95% confidence intervals (CIs) will be estimated using Kaplan-Meier method. Safety parameters will be summarized. The trial is sponsored by HiberCell, Inc. in collaboration with Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Approximately 25 US sites will participate in the study. For information, contact Nick Niles nniles@hibercell.com. 612.230.5846. Citation Format: Alison Stopeck, Michele Gargano, Nandita Bose, Nick Niles, Michael Chisamore, Jose Iglesias. A multicenter, open-label, phase 2 study of Imprime PGG and pembrolizumab in patients with metastatic breast cancer who have progressed through prior hormonal therapy [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-18-05.
e14103 Background: Imprime PGG (Imprime PGG Injection) is a beta-glucan polymer being developed for treatment of cancer in combination with complement-activating monoclonal antibodies. A sequential 2-arm study in CRC patients (pts) evaluated the effects of Imprime PGG administered in combination with cetuximab plus irinotecan (Arm 1) and in combination with cetuximab alone (Arm 2). Results of Arm 1 were previously reported (JCO 27, 2009; abstr e15062). Results of the recently completed Arm 2 are presented here. Methods: Pts with recurrent/progressive CRC (Karnofsky ≥ 70%) previously treated with 5-FU (alone or combined with other therapies) were treated weekly with cetuximab (loading dose 400 mg/m2, then 250 mg/m2) and Imprime PGG and were evaluated in 6-wk cycles. Imprime PGG dosing started at 2 mg/kg and escalated to 4 and 6 mg/kg after safety review. Safety (primary endpoint) was assessed by adverse events (AEs) and efficacy (secondary endpoint) by RECIST. Results: Imprime PGG was dosed in 4 pts at 2 mg/kg and in 9 pts each at 4 and 6 mg/kg. Median age was 57. Of the 22 pts enrolled, 1 pt was discontinued in Week 6 due to protocol violations and 21 pts completed the study. No protocol-defined dose-limiting toxicities were observed. AEs experienced by > 25% of pts included acneiform rash (82%); AST increase (50%), ALP increase, ALT increase, bilirubin increase, and leukocytosis (each 46%); bicarbonate decrease, hypokalemia, paronychia, and pedal edema (each 41%); dry skin and GGT increase (each 36%); anemia and uric acid increase (each 32%); and amylase increase, ANC increase, and hyponatremia (each 27%). No related grade 3 or 4 SAEs were reported. In the per protocol population (n = 21), the overall objective response rate (ORR) was 24% (5 pts), the stable disease rate (SD) was 38% (9 pts) and the disease control rate (ORR + SD) was 62% (13 pts). The median time to progression was 12 wks. Conclusions: Imprime PGG combined with cetuximab in CRC pts was safe and efficacy warrants further investigation. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Biothera Biothera Biothera
Abstract The rate and selectivity found for the hydrogenation reaction of soybean oil using a series of soluble rhodium and iridium‐phosphine complexes can be correlated to the number of phosphine ligands coordinated to the metal. This study shows the possibility of obtaining a wide range of products by varying the reaction time and the catalyst composition. For example, a low stearate content can be obtained using IrCl(C 8 H 12 )PPh 3 , whereas a low double‐bond conjugation can be obtained with |Rh(C 8 H 12 )(PPh 3 ) 2 |BPh 4 .
Abstract 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.
Abstract Imprime PGG is a yeast-derived beta 1,3/1,6 glucan that primes innate immune cells to kill monoclonal antibody (MAb)-targeted cancer cells via a mechanism dependent on complement receptor 3 (CR3). In humans, naturally occurring anti-beta glucan antibodies are required for binding of Imprime PGG to CR3 on immune cells. A quantitative assay has been developed to measure these antibodies in serum; subjects with levels conducive to binding are considered “biomarker positive” (BM+) and others “biomarker negative” (BM-). In a Phase 2 study, stage IIIb or IV NSCLC subjects received cetuximab (250 mg/m2 following initial 400 mg/m2 loading dose) without (Control, N=30) or with Imprime PGG 4mg/kg (Imprime, N=60) on Days 1, 8 and 15 of each 3-week treatment cycle; all subjects also received carboplatin (AUC 6) plus paclitaxel (200 mg/m2) on Day 2 of each cycle for the first 4 to 6 cycles. Maintenance treatment with cetuximab alone or with Imprime was continued in subjects achieving radiographic stable disease or tumor responses (RECIST 1.0). In the efficacy population comprised of all treated subjects who had evaluable baseline and post-baseline scans, median overall survival was 11.2 mo in the control group (N=26), 10.2 mo in the entire Imprime group (N=46) (HR 1.06, p=0.85 vs. control), 16.5 mo in the BM+ Imprime group (N=15) (HR 0.63, p=0.26 vs. control) and 9.1 mo in the BM- Imprime group (N=31) (HR 1.35, p=0.35 vs. control). Three-year survival was 0% in the control group, 7% in the entire Imprime group, 17% in the BM+ Imprime group and 0% in the BM- Imprime group. The objective response rate (ORR, all partial responses) was 23% in the control group, 48% in the entire Imprime group (p= 0.048 vs. control), 67% in the BM+ Imprime group (p=0.009 vs. control) and 39% in the BM- Imprime group (p=0.26 vs. control). Among subjects with squamous cell histology, 6 of 6 BM+ Imprime subjects had responses compared with 3 of 10 control subjects (p=0.01). Grade 3/4 adverse events occurred in 25 of 29 control subjects (86%) and 46 of 59 Imprime subjects (78%). All adverse events were consistent with toxicities attributable to the cytotoxic drugs or cetuximab. In summary, the addition of Imprime PGG to chemoimmunotherapy with carboplatin, paclitaxel and cetuximab resulted in improved outcomes in BM+ subjects with respect to increased ORR and extended survival compared to control subjects and had a good safety profile. Citation Format: Michael Thomas, Parvis Sadjadian, Jens Kollmeier, Zhonglin Hao, Myra Patchen, Jamie Lowe, Paulette Mattson, Richard D. Huhn, Nandita Bose, Mary Antonysamy, Michele Gargano, Keith Gordon, Folker Schneller. Imprime PGG improves the efficacy of carboplatin, paclitaxel, and cetuximab chemoimmunotherapy of advanced non-small cell lung cancer (NSCLC). [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6-9; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2014;20(2Suppl):Abstract nr A26.
