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Ahmed O Kaseb,1 Yinghui Guan,2,&ast; Betul Gok Yavuz,1,&ast; Alexander R Abbas,2 Shan Lu,2 Elshad Hasanov,3 Han Chong Toh,4 Wendy Verret,5 Yulei Wang2 1Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 2Department of Oncology Biomarker Development, Genentech Inc, South San Francisco, CA, USA; 3Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 4Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore; 5Product Development, Genentech Inc, South San Francisco, CA, USA&ast;These authors contributed equally to this workCorrespondence: Yulei Wang, Department of Oncology Biomarker Development, Genentech Inc, 1 DNA Way, South San Francisco, CA, 94080, USA, Tel +1 650 255 9698, Email wang.yulei@gene.com Ahmed O Kaseb, Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 426, Houston, TX, 77030, USA, Tel +1 713 792 2828, Email akaseb@mdanderson.orgPurpose: Child-Turcotte-Pugh class A (CTP-A) in unresectable hepatocellular carcinoma (HCC) is the standard criterion for active therapy and clinical trial enrollment. We hypothesized that insulin-like growth factor-1 (IGF-1) derived scores may provide improved survival prediction over CTP classification. This study aimed to evaluate the potential prognostic and predictive effects of IGF-1 derived scores in the phase III IMbrave150 study.Patients and Methods: Baseline and on-treatment serum IGF-1 levels from 371 patients were subjected to central analysis. Patients’ IGF-1 score (1/2/3) and IGF-CTP score (A/B/C) were determined based on pre-specified cutoffs. Outcomes were analyzed by baseline and by on-treatment changes of the IGF-1 and IGF-CTP scores within and between the two treatment arms. The interaction between these scores and outcomes was assessed using univariate and multivariate analyses.Results: Baseline IGF-CTP score (A vs B/C) showed prognostic significance for OS in both the atezolizumab-bevacizumab (hazard ratio [HR], 0.33; 95% confidence interval [CI], 0.20– 0.56; P< 0.001) and sorafenib (HR, 0.32; 95% CI, 0.16– 0.65; P=0.002) arms. Baseline IGF-1 score (1 vs 2/3) also showed prognostic significance for OS in both the atezolizumab-bevacizumab (HR, 0.33; 95% CI, 0.20– 0.55; P< 0.001) and sorafenib (HR, 0.48; 95% CI, 0.26– 0.89; P=0.02) arms. HRs for PFS were consistent with those for OS. No significant predictive effects were observed for either score between the two arms. Kinetic analysis revealed that patients with increased IGF-1 score (1-> 2/3) at 3 weeks post treatment had shorter OS than patients with stable IGF-1 score of 1 in both the atezolizumab-bevacizumab (HR, 3.70; 95% CI, 1.56– 8.77; P=0.003) and sorafenib (HR, 5.83; 95% CI, 1.88– 18.12; P=0.0023) arms.Conclusion: Baseline and kinetic change of IGF-CTP and IGF-1 scores are independent prognostic factors for patients with unresectable HCC treated with atezolizumab-bevacizumab or sorafenib. These novel scores may provide improved patient stratification in future HCC clinical trials. IMbrave150 ClincialTrials.gov number, NCT03434379.Keywords: IGF-CTP score, prognostic biomarker, immunotherapy, HCC

Background: Hepatocellular carcinoma has high recurrence rates after surgery; however, there are no approved standard-of-care neoadjuvant or adjuvant therapies. Immunotherapy has been shown to improve survival in advanced hepatocellular carcinoma; we therefore aimed to evaluate the safety and tolerability of perioperative immunotherapy in resectable hepatocellular carcinoma. Methods: In this single-centre, randomised, open-label, phase 2 trial, patients with resectable hepatocellular carcinoma were randomly assigned (1:1) to receive 240 mg of nivolumab intravenously every 2 weeks (for up to three doses before surgery at 6 weeks) followed in the adjuvant phase by 480 mg of nivolumab intravenously every 4 weeks for 2 years, or 240 mg of nivolumab intravenously every 2 weeks (for up to three doses before surgery) plus one dose of 1 mg/kg of ipilimumab intravenously concurrently with the first preoperative dose of nivolumab, followed in the adjuvant phase by 480 mg of nivolumab intravenously every 4 weeks for up to 2 years plus 1 mg/kg of ipilimumab intravenously every 6 weeks for up to four cycles. Patients were randomly assigned to the treatment groups by use of block randomisation with a random block size. The primary endpoint was the safety and tolerability of nivolumab with or without ipilimumab. Secondary endpoints were the proportion of patients with an overall response, time to progression, and progression-free survival. This trial is registered with ClinicalTrials.gov (NCT03222076) and is completed. Findings: Between Oct 30, 2017, and Dec 3, 2019, 30 patients were enrolled and 27 were randomly assigned: 13 to nivolumab and 14 to nivolumab plus ipilimumab. Grade 3–4 adverse events were higher with nivolumab plus ipilimumab (six [43%] of 14 patients) than with nivolumab alone (three [23%] of 13). The most common treatment-related adverse events of any grade were increased alanine aminotransferase (three [23%] of 13 patients on nivolumab vs seven [50%] of 14 patients on nivolumab plus ipilimumab) and increased aspartate aminotransferase (three [23%] vs seven [50%]). No patients in either group had their surgery delayed due to grade 3 or worse adverse events. Seven of 27 patients had surgical cancellations, but none was due to treatment-related adverse events. Estimated median progression-free survival was 9·4 months (95% CI 1·47–not estimable [NE]) with nivolumab and 19·53 months (2·33–NE) with nivolumab plus ipilimumab (hazard ratio [HR] 0·99, 95% CI 0·31–2·54); median time to progression was 9·4 months (95% CI 1·47–NE) in the nivolumab group and 19·53 months (2·33–NE) in the nivolumab plus ipilimumab group (HR 0·89, 95% CI 0·31–2·54). In an exploratory analysis, three (23%) of 13 patients had an overall response with nivolumab monotherapy, versus none with nivolumab plus ipilimumab. Three (33%) of nine patients had a major pathological response (ie, ≥70% necrosis in the resected tumour area) with nivolumab monotherapy compared with three (27%) of 11 with nivolumab plus ipilimumab. Interpretation: Perioperative nivolumab alone and nivolumab plus ipilimumab appears to be safe and feasible in patients with resectable hepatocellular carcinoma. Our findings support further studies of immunotherapy in the perioperative setting in hepatocellular carcinoma. Funding: Bristol Myers Squibb and the US National Institutes of Health.

Hepatocellular carcinoma (HCC) is the most common liver cancer and one of the leading causes of cancer-related deaths in the world. Multiple immunotherapeutic approaches have been investigated to date, and immunotherapy has become the new standard of care therapy in HCC. However, the current role of immunotherapy in HCC remains non-curative. Given this context, a high priority for oncology is understanding the biomarkers that predict clinical response to immunotherapy, have the potential to improve patient selection to maximize the clinical benefit, and spare unnecessary toxicity. In this review, we summarize the key predictive and prognostic biomarkers investigated in immunotherapy clinical trials in HCC and the emerging biomarkers to serve as a roadmap for future clinical trials. Biomarkers from tumoral tissues including PDL-1 expression, tissue infiltrating lymphocytes, tumor mutational burden (TMB) and specific immune signatures, and from peripheral blood including neutrophil-to-lymphocytes ratio, platelet-to-lymphocytes ratio, circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), and specific cytokines, along with gut microbiota are among the studied biomarkers to date in the HCC era. More integrative approaches, including mathematical biomarkers to predict immunotherapy outcomes, are yet to be studied in HCC.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and is the second leading cause of cancer-related death worldwide. Fibrosis and cirrhosis are important risk factors for the development of HCC. Hepatic myofibroblasts are the cells responsible for extracellular matrix deposition, which is the hallmark of liver fibrosis. It is believed that myofibroblasts are predominantly derived from hepatic stellate cells (HSCs), also known as Ito cells. Nevertheless, depending on the nature of insult to the liver, it is thought that myofibroblasts may also originate from a variety of other cell types such as the portal fibroblasts (PFs), fibrocytes, hepatocytes, hepatic progenitor cells (HPCs), and mesothelial cells. Liver myofibroblasts are believed to transform into cancer-associated fibroblasts (CAFs) while HCC is developing. There is substantial evidence suggesting that activated HSCs (aHSCs)/cancer-associated fibroblasts (CAFs) may play an important role in HCC initiation and progression. In this paper, we aim to review current literature on cellular origins of myofibroblasts with a focus on hepatitis B virus (HBV)- and hepatitis C virus (HCV)-induced hepatic fibrosis. We also address the role of aHSCs/CAFs in HCC progression through the regulation of immune cells as well as mechanisms of evolvement of drug resistance.

Background Presently, acute myeloid leukemia (AML) risk stratification is estimated prior to treatment by incorporating patient and disease characteristics. However, apart from the limited use of minimal residual disease measurement, few methodologies assess AML relapse risk post-treatment. In attempts to correlate pre- and post-treatment blood cell counts with hematologic disease outcomes, the ratio, LNR, between absolute lymphocyte count (ALC) and neutrophils (ANC) has been utilized to approximate the relationship between the lymphoid system and the myeloid microenvironment (in particular myeloid-derived suppressor cells), and increased LNR is prognostic in myeloma and lymphoma. Similarly, increased LMR (lymphocyte to monocyte ratio), utilized as a crude marker of tumor-infiltrating lymphocytes and tumor-associated macrophages, predicts better outcomes in Hodgkin's disease (Romano et al. Ann Hematol2018). However, analyses correlating such ratios with AML outcomes have not been performed. Here we specifically investigate whether LNR, LMR, or neutrophil-monocyte (NMR) ratios, measured at multiple time-points, correlate with outcomes. Methods We identified patients >18 yrs receiving induction chemotherapy at our institution between 1/1/2005 - 12/31/2019. Data collected included demographics, comorbidities (Charlson Comorbidity Index [CCI]), AML subtype, cytogenetics/molecular data, ELN risk stratification, and response to therapy. We recorded patients' total WBC, ANC, ALC and AMC both prior to treatment, at first ANC recovery (ANC > 1.0 x 109/L with ALC and AMC > 0), and just prior to next therapy. We also identified a subset of patients who received consolidation chemotherapies with curative intent and collected their first WBC counts ~100 days post-therapy completion (range 50-150 days). The calculated LNR, LMR, and NMR at these time-points were correlated with Event-Free Survival (EFS), defined as time to relapse, death from any cause, or last follow-up. Data was censored on 6/1/2020. WBC ratios were categorized into tertiles. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated using Cox proportional hazards models, survivor functions estimated using Kaplan-Meier and the equality of survivor functions tested using stratified log-rank tests. Outcomes were adjusted for CCI, age, sex, race, subtype, presence of inflammation/infection, and ELN risk. Results 145 patients met eligibility criteria, however 23 with primary refractory AML were excluded from EFS analysis. Using WBC ratios at first ANC recovery, both intermediate and high LNR trended towards a lower HR for EFS: HR 0.54 (95% CI 0.24-1.23,p= 0.142) and 0.68 (95% CI 0.32-1.33,p= 0.329), respectively, however differences were not statistically significant (Table 1 and Figure 1). A high NMR also trended towards a worse EFS: HR 1.71 (95% CI 0.74-3.99,p= 0.212), though it was also not statistically significant. LMR did not correlate with improved EFS. Notably, pre-induction ratios and the ratios measured just prior to next treatment were not associated with any differences in EFS. In a subset of patients who received curative intent consolidation chemotherapies (generally ELN favorable risk), a t-test correlating for relapse was performed, though limited by small numbers (16 without, 8 with relapse). Patients in this group who did not relapse trended toward a numerically higher LNR and LMR, 0.57 vs 0.50 (p =0.36) and 4.33 vs 3.97 (p= 0.39), respectively. Discussion In our patient population, high LNR after induction chemotherapy trended towards predicting an improved EFS. Thus, recovery WBC ratios, although crude approximations of the immune system and the tumor microenvironment, may predict patients at higher risk of relapse, however, more patients are clearly needed to show whether a statistically significant association exists. The optimal time to evaluate these counts is also not clear. Nonetheless, as blood counts are obtained routinely post-treatment, these ratios may represent a low-cost strategy to predict relapse risk, potentially allowing for earlier treatment and donor searches for allogeneic transplantation. We propose to repeat these analyses using a multi-center approach - we are especially interested in ratios measured at the 100 days post-therapy mark, as we suspect these may better reflect the immune system at steady state and, potentially, risk of relapse. Disclosures Arain: Astellas:Other: Spouse is employed.Calip:Flatiron Health:Current Employment.Khan:Takeda:Research Funding;Celgene:Consultancy;Incyte:Honoraria;Amgen:Consultancy.Patel:Amgen:Consultancy;Janssen:Consultancy;Celgene:Consultancy.Quigley:Amgen:Other: Advisory board;Agios:Speakers Bureau;Alnylam:Speakers Bureau.

Background:AML is predominantly a disease of the elderly, yet outcomes remain dismal, particularly for relapsed/refractory (R/R) AML patients (pts). Gemtuzumab Ozogamicin (GO) is a monoclonal antibody targeting CD33–commonly expressed on AML blasts, and, critically, AML stem cells (LSC)–linked to the cytotoxin calicheamicin. GO resistance mechanisms include (i) decreased/aberrant blast CD33 expression, (ii) p-glycoprotein export of calicheamicin, and (iii) apoptosis resistance due to deficient activation of mitochondrial outer membrane permeabilization, a process highly dependent on BCL-2 expression. GO-induced apoptosis depends on the pro-apoptotic proteins Bax and Bak and is inhibited by overexpression of the anti-apoptotic proteins BCL-2 or BCL-XL. Venetoclax (VEN) is a BH3 mimetic, binding BCL-2, dislodging its binding to Bak/Bax, and thus facilitating apoptosis. LSC overexpress BCL-2, however VEN monotherapy is not effective in AML, as resistance develops rapidly. Hypothesis: VEN targeting of BCL-2 proteins that protect LSC from GO-induced apoptosis will synergistically increase GO efficacy. Correlative studies include pre-treatment AML blast BH3 profiling, CD33 expression (including sequencing for isoforms), and BCL-2, BCL-XL, and MCL-1 protein levels; MRD measurement at post-therapy time points using digital drop PCR technology; and quality of life assessments (EORTC QLQ-C30, FACT-Fatigue) Methods:This is a single arm, open-label, multi-center (BTCRC), dose-escalation phase Ib study of combination of VEN and GO in R/R AML pts (18-75y), using a 3+3 design. Major eligibility: ECOG 0-2, adequate organ function, CD33+ in ≥ 20% AML blasts, ≤ 3 lines of prior therapy, and no prior use of GO or VEN, previous VOD, BMT within 2 months, CNS disease, or history of HIV. Induction: 3-day VEN ramp-up to the target dose of 200 (cohort i), 400 (ii), or 600 (iii) mg daily x 28 d, with GO 3mg/m2 infused days 1, 4, and 7. If CR/CRi achieved, pts proceed to BMT if applicable, otherwise, if in CR/CRi (provided ANC > 1000, plts > 100K) or PR (regardless of counts), they are consolidated with VEN at the prescribed dose x 28d and GO 3mg/m2 on days 1 and 4 (Cycle 2). If BMT not applicable, and pt remaining in CR/CRi or PR (as above), then proceed to VEN alone as Maintenance in cycles 3+ until progression or toxicity. The primary endpoint is MTD of VEN with GO. Secondary endpoints include ORR, anti-leukemic activity, characterization of AEs, and estimates of RFS, EFS, and OS. Progress: This study is currently open to its second dosing cohort and has enrolled 5 pts to date. No dose-limiting toxicities have been encountered. However, the COVID-19 pandemic has had a negative impact on enrollment, which is expected to improve as vaccinations expand. ClinicalTrials.gov NCT04070768. Citation Format: Saad Arain, Pritesh Patel, Karen Sweiss, Brian Parkin, Heiko Konig, Gregory Calip, Betul Gok Yavuz, John Quigley. Phase Ib study of the safety and efficacy of Gemtuzumab Ozogamicin (GO) and Venetoclax in patients with relapsed or refractory CD33+ acute myeloid leukemia: Big Ten Cancer Research Consortium BTCRC-AML17-113 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT224.

Fibroblasts turn into cancer associated fibroblasts (CAFs) in the tumour microenvironment. CAFs have recently attracted attention for their function as a regulator of immune cell recruitment and function in addition to their tumour-promoting roles. In this study, we aimed to determine the role of CAFs on monocyte recruitment and macrophage polarization in breast cancer. CAFs, which were α-SMA expressing fibroblasts in contrast to normal fibroblasts (NFs), effectively recruited monocytes. Recruitment of monocytes by CAFs might be mediated by monocyte chemotactic protein-1 (MCP-1) as well as stromal cell-derived factor-1 (SDF-1) cytokines. CAFs differentiated the recruited monocytes into M2-like macrophages which are capable of exerting their immunosuppressive roles via the PD-1 axis. CAF-educated monocytes exhibited strong immune suppression unlike NF-educated monocytes and enhanced the motility/invasion of breast cancer cells in addition to increasing the expressions of epithelial–mesenchymal transition (EMT)-related genes and vimentin protein in cancer cells. CAF-educated M1 macrophages displayed increased expression of M2 markers and production of anti-inflammatory cytokine IL-10 in contrast to decreased production of pro-inflammatory cytokine IL-12 compared with control M1 macrophages; suggesting that CAFs were also able to induce the trans-differentiation of M1 macrophages to M2 macrophages. We then investigated the relationship between the infiltration of CAFs and tumour associated macrophages (TAMs) using tissue samples obtained from breast cancer patients. High grade of CAFs significantly correlated with the number of TAMs in human breast cancer tissue samples. It was also associated with higher Ki-67 proliferation index, and higher tumour volume. This result is in line with our finding of increased breast cancer cell proliferation due to the effects of CAF-educated monocytes in vitro. Our results concluded that CAFs play pivotal roles in sculpturing the tumour microenvironment in breast cancer, and therapeutic strategies to reverse the CAF-mediated immunosuppressive microenvironment should be taken into consideration.