Pollak, Michaël

Abstract Consumption of a Western diet and high body mass index (BMI) are risk factors for progression from premalignant phenotypes to multiple myeloma, a hematologic cancer. In the NUTRIVENTION trial (NCT04920084), we administered a high-fiber, plant-based diet (HFPBD; meals for 12 weeks, coaching for 24 weeks) to 23 participants with myeloma precursor states and elevated BMI. The intervention was feasible and improved quality of life and modifiable risk factors: metabolic (BMI, insulin resistance), microbiome (diversity, composition), and immune (inflammation, monocyte subsets). Disease progression trajectory improved (n = 2) or was stable. Findings were translated to Vk*MYC mice modeling the myeloma precursor state, in which a high-fiber diet (HFD) delayed disease progression through improved metabolism and microbiome composition, leading to increased short-chain fatty acid production that reinvigorated antitumor immunity and inhibited tumor growth. These effects from fiber consumption were independent of calorie restriction and weight loss. A HFD is a low-risk intervention that may delay progression to myeloma. Significance: A HFPBD in participants with precursor plasma cell disorders and an elevated BMI improved metabolic, microbiome, and immune biomarkers of disease. In a subset, it may delay progression to myeloma. In mouse models, a HFD delayed progression to myeloma independent of calorie restriction. See related commentary by Fairfield and Reagan, p. 623

Introduction Poor diet quality, elevated body mass index (BMI), insulin resistance, microbiome dysbiosis, inflammation as well as immune dysfunction have all been implicated in progression from monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) to multiple myeloma (MM). Plant-based diets have been associated with reduced risk of MGUS and MM in epidemiological studies. Whether a dietary intervention can impact these modifiable risk factors and delay disease progression has not been investigated. Methods We conducted a pilot, single-arm trial providing controlled high fiber plant based dietary (HFPBD) intervention for 12 weeks and health coaching for 24 weeks in 20 patients with MGUS/SMM with BMI≥25 (NCT04920084). The primary endpoint was feasibility (adherence and BMI reduction). Secondary and exploratory endpoints included quality of life, metabolic markers (insulin, adiponectin, leptin, LDL cholesterol), microbiome (diversity and composition by 16S and shotgun sequencing) and immune profiling in peripheral blood (flow cytometry and Olink inflammation panel) and bone marrow (scRNAseq and ATACseq). We also conducted an in vivo study in transgenic Vk*MYC mice fed a high fiber or control diet at the phase of mouse(m)SMM. The mice were monitored for the progression to active mMM. Differences in microbiome and immune response profiles between high fiber- and control-treated mice were assessed via microbiome 16S sequencing and flow cytometry. Results The HFPBD intervention was safe, feasible, improved quality of life and addressed modifiable risk factors - metabolic profile (improved BMI, insulin resistance, adiponectin leptin ratio), microbiome profile (increased alpha-diversity and butyrate producers) and immune (decreased inflammation and increased anti-inflammatory classical monocyte) subsets. A reduction in long-term progression trajectory was observed in 2 patients. Consistently, the high fiber diet delayed progression from mSMM to mMM in Vk*MYC mice increasing median progression-free survival from 12 weeks in the control arm to 30 weeks in the high fiber diet intervention arm. Additionally, in the intervention arm 40% of mice did not progress to mMM during the study period whereas all mice in the control arm progressed. Both human and mouse data showed that HFPBD modulated gut microbiota composition favoring the expansion of butyrate-producing bacteria. Additionally, short-chain fatty acids were increased in the feces of mice fed a high fiber diet. Integrated analysis from human bone marrow and peripheral blood analysis indicated that the dietary intervention reduced inflammatory biomarkers and skewed the immune response towards T helper and CD14+ monocytes. Consistently, the bone marrow of Vk*MYC mice fed high fiber diet was more infiltrated by IFNg-producing T lymphocytes while displaying less exhausted T cells and immunosuppressive myeloid cells. Conclusion This is the first interventional clinical trial and in vivo study to show that a HFPBD intervention may delay progression from MGUS/SMM to MM. To our knowledge there has been no similar dietary interventional study in hematological cancers or solid tumors. Together our in vivo and clinical data support the beneficial anti-inflammatory role of a HFPBD providing a link between diet, microbiota, and immune modulation to delay disease progression in MGUS/SMM.

Abstract To investigate whether insulin-like growth factor (IGF)-1 and IGF-binding protein-3 (IGFBP-3) are prospectively associated with exocrine pancreatic cancer, we conducted a nested case-control study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort of 29,133 male Finnish smokers, aged 50–69 years. To avoid the potential influence of subclinical cancer on IGF-1 and IGFBP-3, all subjects in this study were alive without clinical evidence of cancer during their 5th year of the cohort follow-up. Four hundred randomly selected cohort controls and 93 incident pancreatic adenocarcinoma cases that occurred between their 5th follow-up year through 1997 (i.e., up to 12.7 years of follow-up) were included in this study. Concentrations of IGF-1 and IGFBP-3 were measured in serum samples obtained at baseline using ELISA. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression models, adjusted for confounders. Neither IGF-1, IGFBP-3, nor the IGF-1:IGFBP-3 molar ratio was significantly associated with pancreatic cancer: highest compared to lowest tertile, OR = 0.67, 95% CI 0.37–1.21, P trend = 0.17; OR = 0.70, 95% CI 0.38–1.27, P trend = 0.12; and OR = 0.85, 95% CI 0.50–1.46, P trend = 0.54, respectively. Our results do not support the hypothesis that serum IGF-1 and IGFBP-3 concentrations are associated with pancreatic cancer risk among male smokers. Further studies are necessary to evaluate these associations in other populations.

AbstractBackgroundAdipocyte-derived adiponectin may play a role in the host inflammatory response to cancer. We examined the association of plasma adiponectin with the density of tumor-infiltrating lymphocytes (TILs) in colon cancers and with vitamin D, clinicopathological features, and patient survival.MethodsPlasma adiponectin and 25-hydroxyvitamin D [25(OH)D] were analyzed by radioimmunoassay in 600 patients with stage III colon cancer who received FOLFOX-based adjuvant chemotherapy (NCCTG N0147 [Alliance]). TIL densities were determined in histopathological sections. Associations with disease-free survival (DFS), time to recurrence, and overall survival were evaluated by multivariable Cox regression adjusting for potential confounders (ie, body mass index, race, TILs, and N stage). All statistical tests were 2-sided.ResultsWe found a statistically significant reduction in adiponectin, but not 25(OH)D, levels in tumors with high vs low TIL densities (median = 6845 vs 8984 ng/mL; P = .04). A statistically significant reduction in adiponectin was also observed in obese (body mass index >30 kg/m2) vs nonobese patients (median = 6608 vs 12 351 ng/mL; P < .001), in men vs women (median = 8185 vs 11 567 ng/mL; P < .001), in Blacks vs Whites or Asians (median = 6412 vs 8847 vs 7858 ng/mL; P < .03), and in those with fewer lymph node metastases (N1 vs N2: median = 7768 vs 9253 ng/mL; P = .01). Insufficiency of 25(OH)D (<30 ng/mL) was detected in 291 (48.5%) patients. In multivariable analyses, neither adiponectin nor 25(OH)D were associated with a statistically significant difference in DFS, overall survival , or time to recurrence in models adjusted for potential confounders. We found a statistically significant association of TILs with prognosis, yet no such interaction was observed for the association of adiponectin with TILs for DFS.ConclusionsLower circulating adiponectin levels were associated with a statistically significant increase in TIL densities in colon cancers, indicating an enhanced antitumor immune response. In contrast to TILs, neither adiponectin nor 25(OH)D was independently prognostic.

3591 Background: Adiponectin is a peptide hormone exclusively secreted by adipocytes that plays a role in immune regulation and in the host inflammatory response to cancer. We examined postsurgical adiponectin levels in relationship to tumor infiltrating lymphocytes (TILs), clinicopathological features, vitamin D status, and patient survival in participants in a phase 3 trial of adjuvant chemotherapy. Methods: Plasma adiponectin and 25-hydroxyvitamin D [25(OH)D] were analyzed by radioimmunoassay in 600 patients with stage III colon carcinoma who received adjuvant FOLFOX +/- cetuximab. TIL densities were determined at light microscopy in routine histopathological sections. The associations between adiponectin and 25(OH)D, TILs, other factors were evaluated by Fisher’s Exact, Chi-squared, t-test, and Kruskal-Wallis tests where appropriate. The association between adiponectin or 25(OH)D with disease-free survival (DFS), time to recurrence (TTR) and overall survival (OS) were evaluated by multivariable Cox regression, adjusting for body mass index (BMI), race, T, N stage, performance status, tumor location, TILs, BRAF/KRAS, and mismatch repair status. Results: A statistically significant and inverse association between adiponectin level and BMI was observed with lower levels found with obesity (BMI > 30 kg/m2) [p < 0.001]. The level of adiponectin was significantly lower in men vs women (p < 0.001), in blacks vs whites or Asians (p < 0.032), and in patients with fewer regional lymph node metastases (N1 vs N2 stage, p = 0.011). A significantly lower level of adiponectin was found in patients whose tumors had high vs low TIL densities (p = 0.040), but was unrelated to 25(OH)D. Insufficiency of 25(OH)D ( < 30 ng/ml) was detected in 291 (49%) of patients and was not associated with TILs. By multivariable analysis, adiponectin was not associated significantly with patient DFS (HRadj= 0.98, 95% CI 0.74-1.29, padj= 0.88) nor with OS nor time-to-recurrence (TTR). TIL densities were significantly prognostic, but 25(OH)D was not (DFS: HRadj= 1.12, 95% CI 0.85-1.47, padj= 0.44). No significant interaction was observed for adiponectin with TILs for the association with DFS. Conclusions: Lower adiponectin levels were associated with significantly increased TIL densities in colon cancers, indicating an enhanced anti-tumor immune response. In contrast to TILs, adiponectin was not independently associated with patient outcome. Nearly one-half of stage III patients were vitamin D insufficient, although 25(OH)D was not prognostic.

AbstractBackgroundEnergy balance-related biomarkers are associated with risk and prognosis of various malignancies. Their relationship to survival in metastatic colorectal cancer (mCRC) requires further study.MethodsBaseline plasma insulin-like growth factor (IGF)-1, IGF-binding protein (IGFBP)-3, IGFBP-7, C-peptide, and adiponectin were measured at time of trial registration in a prospective cohort of patients with mCRC participating in a National Cancer Institute–sponsored trial of first-line systemic therapy. We used Cox proportional hazards regression to adjust for confounders and examine associations of each biomarker with overall survival (OS) and progression-free survival (PFS). P values are 2-sided.ResultsMedian follow-up for 1086 patients was 6.2 years. Compared with patients in the lowest IGFBP-3 quintile, patients in the highest IGFBP-3 quintile experienced an adjusted hazard ratio (HR) for OS of 0.57 (95% confidence interval [CI] = 0.42 to 0.78; Pnonlinearity &lt; .001) and for PFS of 0.61 (95% CI = 0.45 to 0.82; Ptrend = .003). Compared with patients in the lowest IGFBP-7 quintile, patients in the highest IGFBP-7 quintile experienced an adjusted hazard ratio for OS of 1.60 (95% CI = 1.30 to 1.97; Ptrend &lt; .001) and for PFS of 1.38 (95% CI = 1.13 to 1.69; Ptrend &lt; .001). Plasma C-peptide and IGF-1 were not associated with patient outcomes. Adiponectin was not associated with OS; there was a nonlinear U-shaped association between adiponectin and PFS (Pnonlinearity = .03).ConclusionsAmong patients with mCRC, high plasma IGFBP-3 and low IGFBP-7 were associated with longer OS and PFS. Extreme levels of adiponectin were associated with shorter PFS. These findings suggest potential avenues for prognostic and therapeutic innovation.

3587 Background: The Insulin like Growth Factor I receptor (IGF-IR), a tyrosine kinase, is widely expressed in human tissues. IGF- IR and its ligands (IGF-I and IGF-II) are expressed by many human cancers (e.g., breast, prostate, colorectal and non-small cell lung). Binding of the ligands to the IGF-IR activates key cellular signaling pathways important for stimulating cellular proliferation and inhibiting apoptosis. IGF- I and IGF-II are present in the circulation, but also locally expressed in neoplastic tissue. Bioavailability of these ligands is regulated by a family of IGF binding proteins (IGFBPs1–6). CP-751,871, a fully human monoclonal antibody, is a highly specific and potent inhibitor of IGF-IR activation. In vitro experiments show that binding of CP 751,871 to IGF-IR induces receptor internalization and degradation. This antibody has been shown to have antineoplastic activity using both in vivo and in vitro pre-clinical models. Methods: Blood samples were collected for characterization of the pharmacokinetic and pharmacodynamic properties of CP-751,871 in phase 1 trials of this agent given to cancer patients either alone or in combination with chemotherapy. The endpoints assessed included among others: CP-751,871 plasma concentrations, total and free IGF-I, IGFBP-3, soluble IGF-IR and IGF-IR expression on granulocytes and tumor cells. Results: CP 751,871 exposure increased with dose over the 800-fold dose range investigated. Pharmacokinetic profiles were consistent with target-mediated disposition. A dose-dependent downregulation of soluble IGF-IR serum concentration and IGF-IR expression was observed, with sustained inhibition for the entire dosing period (3–4 week cycles) observed at doses ≥ 1.5 mg/kg. As predicted for an agent that interferes with IGF-I action, IGF-I and IGFBP-3 serum levels were up-regulated in a similar dose-dependent manner. Conclusions: The pharmacodynamic endpoints of clinical trials provide evidence that CP-751,871 targets IGF-IR in granulocytes, tumor cells and tissues involved in regulation of the growth hormone -IGF-I axis. These data provide proof of principle for the use of CP-751,871 as a first-in-class therapeutic approach to inhibit the IGF-IR pathway in cancer patients. No significant financial relationships to disclose.

3507 Purpose: To detect IGF-1R on circulating tumor cells (CTCs) as a biomarker in the clinical development of a monoclonal human antibody, CP-751,871, targeting IGF-1R. Experimental Design: An automated sample preparation and analysis system for enumerating CTCs (Celltracks) was adapted for detecting IGF-1R positive CTCs with a diagnostic antibody targeting a different IGF-1R epitope to CP-751,871. This assay was utilized in three phase I trials of CP-751,871 as a single agent or with chemotherapy and was validated using cell lines and blood samples from healthy volunteers and patients with metastatic carcinoma. Results: There was no interference between the analytical and therapeutic antibodies. CP-751,871 was well tolerated as a single agent, and in combination with docetaxel or carboplatin and paclitaxel, at doses ranging from 0.05 mg/kg to 20 mg/kg. Eighty patients were enrolled on phase 1 studies of CP-751,871, with 47 (59%) patients having CTCs detected during the study. Prior to treatment 26 patients (33%) had CTCs, with 23 having detectable IGF-1R positive CTCs. CP-751,871 alone, and CP-751,871 with cytotoxic chemotherapy, decreased CTCs and IGF-1R positive CTCs; these increased towards the end of the 21-day cycle in some patients, falling again with retreatment. CTCs were commonest in advanced hormone refractory prostate cancer (11/20). Detectable IGF-1R expression on CTCs before treatment with CP-751,871 and docetaxel was associated with a higher frequency of PSA decline by more than 50% (6/10 vs 2/8 patients). A relationship was observed between sustained falls in CTCs counts and PSA declines by more than 50%. Conclusions: IGF-1R expression is detectable by immunofluorescence on CTCs. These data support the further evaluation of CTCs in pharmacodynamic studies and patient selection, particularly in advanced prostate cancer. No significant financial relationships to disclose.

Abstract Background: CP-751,871, a fully human IgG2 subtype monoclonal antibody, is a potent and specific inhibitor of the insulin- like growth factor type I receptor (IGF-IR). The IGF-IR regulates the growth, survival, adhesion and invasiveness of multiple myeloma cells. High IGF-IR expression is observed in poor-prognostic subtypes of multiple myeloma and its inhibition has been long proposed as a potential therapeutic approach for treatment of this disease. Methods: A phase 1 dose escalation study was conducted to define the safety and tolerability, and to characterize the pharmacokinetic and pharmacodynamic (granulocyte surface IGF-IR expression and serum IGF-I levels) properties of CP-751,871 in patients with multiple myeloma. Patient’s eligibility included previously treated multiple myeloma in relapse or refractory phase including those less than complete remission to autologous stem cell transplant or tandem transplant. Results: Following informed consent and screening, 47 patients were enrolled into 11 dose-escalation cohorts of CP-751,871 at doses from 0.025 to 20 mg/Kg. Median patient age was 60 years. Median number of previous regimens was 4 (range 1–8). CP-751,871 was given as an IV infusion on Day 1 of 4-week cycles. Patients with a suboptimal response to CP-751,871 alone were eligible to receive CP-751,871 in combination with either oral dexamethasone and/or rapamycin at the discretion of the investigator. Twenty-seven patients received CP-751, 871 in combination with dexamethasone, while four patients received rapamycin in combination with either CP-751,871 or CP-751,871 and dexamethasone. Median number of treatment cycles was 3 (range 1–16). Ten patients were dosed at the highest cohort of 20 mg/Kg. No CP-751,871 related dose limiting toxicities were identified. Grade 3 toxicities were all observed at the 20 mg/Kg cohort (1 hyperglycemia, 1 anemia, 1 AST increase, 1 accidental fall, 1 muscle weakness). Plasma CP-751,871 exposure increased with dose, and the pharmacokinetic characteristics were consistent with target-mediated disposition. Granulocyte IGF-IR expression was maximally down-regulated for the entire duration of the dosing period at doses ≥1.5 mg/kg, indicating a saturation of circulating targets. CP-751,871 also led to a dose-dependent increase in circulating IGF-I concentrations. Tumor response was assessed according to Blade criteria. Two remissions and 4 partial remissions were reported in patients treated with different doses of CP-751,871 in combination with dexamethasone. Interestingly, the 2 patients with remission were previously found to be refractory to dexamethasone treatment. Conclusions: These data indicate that CP-751,871 is well tolerated either as a single agent or in combination with dexamethasone. Furthermore, CP-751,981 in combination with dexamethasone, may constitute a novel and effective therapeutic approach for patients with multiple myeloma.