This manuscript reports the results of a phase I clinical trial combining intratumoral vidutolimod, hypofractionated radiotherapy, nivolumab and ipilimumab in MSS mCRC. Of the 19 patients accrued, none responded, aside from 1 patient, attributed to high tumor mutational burden. The juxtaposition of liver irradiation and intratumoral vidutolimod injection was associated with hepatic toxicity.Introduction: Microsatellite stable metastatic colorectal cancer (MSS mCRC) is largely refractory to immune checkpoint inhibition. We hypothesized that a combination of intratumoral TLR9 agonist, radiosurgery and dual PD-1 and CTLA-4 blockade would induce a local focus of immune stimulation, evoking a systemic immune response.Patients and Methods: In this phase I single-institution study, patients with MSS mCRC were treated with a priming dose of s.c vidutolimod, 3 intratumoral injections of vidutolimod and radiosurgery, combined with nivolumab and ipilimumab. Cytokine levels were measured at baseline and at 7 (+/- 2) weeks. Patients were accrued to 4 consecutive cohorts: (1) Safety run-in without radiosurgery, (2) Radiosurgery prior to intratumoral therapy, (3) Radiosurgery prior to intratumoral therapy with a condensed timeline, and (4) Radiosurgery to extrahepatic lesion following completion of intratumoral therapy.Results: A total of 19 patients were accrued. Median age was 59 years (range 40-71), 68% were male, median number of previous systemic treatments was 3 (range 2-5). None of the patients responded, aside from 1 patient, attributed to high tumor mutational burden. Grade 3 liver toxicity was reported in 0%, 0%, 75%, and 17% in cohorts 1 to 4, respectively. Systemic levels of CXCL10 and IL-10 increased, with a median of 407 versus 78 pg/mL ( P = .01), and 66 versus 40 pg/mL ( P = .03), respectively. Conclusions: The combination of intratumoral vidutolimod, radiosurgery, nivolumab and ipilimumab was not found to be efficacious in MSS mCRC with liver metastases. The juxtaposition of liver irradiation and intratumoral vidutolimod injection was associated with high hepatic toxicity.

123 Background: Microsatellite stable (MSS) or mismatch repair proficient (MMR-P) metastatic colorectal cancer is refractory to immune checkpoint inhibition. We hypothesized that a combination of intratumoral TLR9 agonist, radiosurgery and dual PD-1 and CTLA-4 blockade would induce a local focus of immune stimulation, evoking a systemic immune response. Methods: In this single institution investigator-initiated phase I study, patients with MSS / MMR-P metastatic colorectal cancer were treated with a priming dose of subcutaneous (s.c.) vidutolimod, three intratumoral injections of vidutolimod, and radiosurgery to a metastasis, combined with nivolumab 3mg/kg every 2 weeks and ipilimumab 1 mg/kg every 6 weeks. Following conclusion of intratumoral therapy, s.c. injections of vidutolimod commenced. Efficacy endpoints were based upon a non-irradiated and non-injected lesion. Cytokine levels were measured at baseline and at 7 (± 2) weeks. Patients were placed in 4 cohorts: (1) Safety run-in without radiosurgery (No RT); (2) Radiosurgery prior to intratumoral therapy (Early Liver RT Slow). An amendment was made due to early patient fall-out due to progressive disease; (3) Radiosurgery prior to intratumoral therapy with a condensed timeline (Early Liver RT Quick). An additional amendment was made due to unacceptable liver toxicity; (4) Radiosurgery to extrahepatic lesion following completion of intratumoral therapy (Late Extrahepatic RT). ClinicalTrials.gov Identifier NCT03507699. Results: A total of 19 patients were accrued (No RT, n=2; Early Liver RT Slow, n=7; Early Liver RT Quick, n=4; Late Extrahepatic RT, n=6). Median age was 59 years (range 40-71), 68% were male, median number of previous systemic treatments was 3 (range 2 – 5). None of the patients responded, aside from one patient in cohort #4 who achieved complete response, and was subsequently found to have a high tumor mutational burden (TMB) 79 mutations / Mb. Grade 3 liver toxicity, including elevated transaminases and hyperbilirubinemia, was reported in 0%, 0%, 75% and 17% in cohorts 1-4, respectively. Reactions following intratumoral injections, typically within 12 hours, included fever (68%), tachycardia (21%), chills (63%) and hypotension (47%). There was an increase in systemic CXCL10 levels at 7 (± 2) weeks compared to baseline, with a median of 407 versus 78 pg/ml, respectively, p<0.01. Conclusions: Intratumoral liver injection of vidutolimod was associated with acute systemic symptoms attributed to cytokine release. The juxtaposition of liver irradiation and intratumoral vidutolimod injection to the same lesion was associated with unacceptable hepatic toxicity. The combination of intratumoral vidutolimod, radiosurgery, nivolumab and ipilimumab was not found to be efficacious in MSS / MMR-P colon cancer. Clinical trial information: NCT03507699 .

Background Neoadjuvant immune checkpoint inhibitor treatment is a promising approach for resectable cancer, including non-small cell lung cancer (NSCLC). The characteristics of potential responders to such treatments and the molecular underlying events are not known. Methods We have conducted a phase I, investigator-initiated single-center study (MK3457-223), to examine the safety of neoadjuvant pembrolizumab for stage I-II resectable NSCLC and to determine the recommended phase II dose/schedule (RP2D/S). FFPE biopsies and surgical specimens were subjected to correlative studies. NanoString’s GeoMx Digital Spatial Profiler (DSP) analysis was conducted on pre-treatment samples and post-treatment responder samples. Protein (72 proteins) and mRNA expression data (73 genes) analysis was conducted on regions of interest (ROIs), defined as mostly CD8 positive or mostly pan-cytokeratin positive (presumed cancer cells). Pathology assessment was done on the surgical specimen to identify major pathologic response (MPR; ≤10% remaining viable cells). Statistical analysis was done to compare responders (MPR+) to non-responders (MPR-) by Mann Whitney with false discovery rate correction. Immunohistochemistry (IHC) was conducted on post-treatment samples. Results Twenty-six patients initiated treatment on the study. Two patients (8%, 95% C.I 0-18%) had adverse events that precluded surgery, 1 patient refused surgery after treatment. 7 patients (27%, 95% C.I 10-44%) achieved a major pathologic response (MPR; responders), 3 patients (12%, 95% C.I 0-24%) achieved complete pathologic response. Responders had a longer interval from treatment to surgery (43 days vs. 36 days, univariate analysis, p-value 0.043). RP2D/S was determined as 2 treatments of 200mg pembrolizumab at 3 week interval, followed by surgery at least 2 weeks later. The expression of several proteins and genes differed between responders and non-responders. Pre-treatment, CD20 protein was the most differentially expressed protein both in in CD8+ (4.7 fold, p=0.002) and in cancer cells (4.8 fold, p=0.001) ROIs, in both cases higher in the responders compared to the non-responders. Comparing pre to post-treatment expression in responding tumors, the protein found to be upregulated to the highest extent following pembrolizumab treatment was CD20 protein (6.2-fold, p=0.001), as was its encoding gene, MS4A1 (2.4-fold, p=0.006). CD20 IHC of post-treatment samples demonstrated tertiary lymphoid structures (TLS) to be more prevalent in responders compared to non-responders (3.2-fold, p<0.05). Conclusions Longer interval from treatment to surgery was associated with higher rate of MPR. Presence of tumor-infiltrating B-cells and evolvement of TLSs was strongly correlated with pathologic response to neoadjuvant pembrolizumab in early stage NSCLC. Citation Format: Jair Bar, Iris Kamer, Oranit Zadok, Damien Urban, Marina Perelman, Ilanit Redinsky, Aliza Ackerstein, Sameh Daher, Efrat Ofek, Amir Onn, Nona Zeitlin, Alon Ben-Nun, Ran Kremer, Inbal Daniel, Yossef Glantzspiegel, Irit Gat-Viks. B-cell infiltration in lung cancer predicts response to neoadjuvant pembrolizumab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT154.

Protein mislocalization is a frequent, yet underappreciated, characteristic of cancer, 1 Wang X Li S. Protein mislocalization: Mechanisms, functions and clinical applications in cancer. Biochim Biophys Acta. 2014; 1846: 13-25 PubMed Google Scholar leading to both gain and loss of function; tumor suppressor proteins such as p53 and adenomatous polyposis coli are ineffective when mislocated out of the nucleus. The eukaryotic protein exportin 1 (XPO1) plays a critical role in regulating the export of proteins and RNAs from the nucleus to the cytoplasm. 2 Azmi AS Uddin MH Mohammad RM. The nuclear export protein XPO1—from biology to targeted therapy. Nat Rev Clin Oncol. 2021; 18: 152-169 Crossref PubMed Scopus (88) Google Scholar XPO1 dysregulation plays a pivotal role in both the development of various malignancies and their resistance to many chemotherapeutic agents. Selinexor (KPT-330, Xpovio) is an oral, first-in-class, selective inhibitor of XPO1-mediated nuclear export compound. Selinexor leads to nuclear retention of both tumor suppressor proteins and oncoprotein mRNAs (eg, c-myc, Bcl family proteins), promoting cancer cell apoptosis (Fig. 1) 2 Azmi AS Uddin MH Mohammad RM. The nuclear export protein XPO1—from biology to targeted therapy. Nat Rev Clin Oncol. 2021; 18: 152-169 Crossref PubMed Scopus (88) Google Scholar and augmenting the activity of many chemotherapeutic agents. 3 Turner JG Dawson JL Grant S et al. Treatment of acquired drug resistance in multiple myeloma by combination therapy with XPO1 and topoisomerase II inhibitors. J Hematol Oncol. 2016; 9: 73 Crossref PubMed Scopus (57) Google Scholar ,4 Quintanal-Villalonga A Taniguchi H Hao Y et al. Inhibition of XPO1 sensitizes small cell lung cancer to first- and second-line chemotherapy. Cancer Res. 2022; 82: 472-483 Crossref PubMed Scopus (13) Google Scholar Moreover, selinexor acts as a radiosensitizer across diverse cell types, including rectal cancer; proposed mechanisms include impaired DNA damage repair, 5 Kashyap T Argueta C Unger T et al. Selinexor reduces the expression of DNA damage repair proteins and sensitizes cancer cells to DNA damaging agents. Oncotarget. 2018; 9: 30773-30786 Crossref PubMed Scopus (39) Google Scholar possibly due to a global inhibition of gene translation 6 Wahba A Rath BH O'Neill JW Camphausen K Tofilon PJ The XPO1 inhibitor selinexor inhibits translation and enhances the radiosensitivity of glioblastoma cells grown in vitro and in vivo. Mol Cancer Ther. 2018; 17: 1717-1726 Crossref PubMed Scopus (29) Google Scholar and promotion of apoptosis. 7 Ferreiro-Neira I Torres NE Liesenfeld LF et al. XPO1 inhibition enhances radiation response in preclinical models of rectal cancer. Clin Cancer Res. 2016; 22: 1663-1673 Crossref PubMed Scopus (36) Google Scholar Selinexor has yet to be combined with radiation in humans. The drug was recently approved by the Food and Drug Administration for the treatment of multiple myeloma and diffuse large B-cell lymphoma.

e14149 Background: Oncologists often need an objective, quantitative assessment of a patient's response to therapy. Lacking a standardized format, the oncologist may request a RECIST (Response Evaluation Criteria in Solid Tumors) analysis. RECIST, however, was developed to provide standardized assessment in the context of randomized clinical trials. RECIST is based on the prospective analysis of a limited sample of tumor lesions or lymph nodes, whereas the clinician naturally makes clinical decisions retrospectively. Furthermore, RECIST has definitions, rules, and criteria for classifying responses that may not apply in the clinical setting, and it does not include consistent rules for merging or splitting lymph nodes, mixed tumor responses, lesions that may cavitate, and a wide range of individualistic responses encountered in clinical practice. Methods: To address these issues, we have modified our working Excel-based template for RECIST 1.1 assessment to include a "myRECIST" feature, so that the radiologist can enter data and examine a range of pre-defined or customizable scenarios, including RECIST1.1, iRECIST, Lugano, volumetric and other parametric protocols. With a few interactions, this template can produce exportable tables and graphs of tumor responses that can guide therapy, as shown in the attached image. Definitions are standardized and linked to RADLEX ontology for specificity and subsequent analysis. Results: This template has been developed for clinical use and is available for downloading from our institutional web-site. Conclusions: We have developed, for public use, a free, easy-to-use, down-loadable Excel template for evaluating prospective or retrospective scenarios of tumor response to therapy that avoids the restrictions of the RECIST methodology. This template may prove useful to oncologists both in and out of the context of randomized clinical trials. We call this "myRECIST."

This chapter presents several alternative therapeutic approaches based on passive adoptive transfer of immunocompetent donor allogeneic bone marrow or peripheral blood lymphocytes (PBL) or in vitro activated allogeneic PBL, with or without further in vivo activation of effector cells with recombinant human interleukin 2. The role of allogeneic cell-therapy in conjunction with BMT is best documented by comparing the rate of relapse of patients undergoing syngeneic and autologous BMT in comparison with allogeneic BMT, both being conditioned by identical myeloablative protocols. After induction of stable chimerism recipients are expected to accept donor lymphocytes and permit induction of effective graft vs-leukemia. The use of adoptive allogeneic cell therapy for the treatment of cancer represents the beginning of a new era in applying biological therapy of cancer. In the future, tumor-selective effector cells may be obtained by choosing well-defined T cell subsets, with possible further in vitro expansion and activation of anti-cancer effector cells.

8534 Background: Resected NSCLC clinical stage I or II harbor a 5 year survival of only 30-50%. Immunotherapy might be more effective in low-burden disease. We hypothesized that neo-adjuvant immunotherapy is a feasible, safe and effective treatment (Tx) for early stage NSCLC. Methods: MK3475-223 is an ongoing phase I study of neoadjuvant pembrolizumab in stage I-II NSCLC. All Pembro Txs are 200mg q 3 weeks (wks). Objectives: determine safety; recommended phase 2 dose/schedule; pathological & radiological response. Doses-schedule limiting toxicities (DLT) were defined as significant surgical complications (bleeding, delayed wound healing, ARDS, prolonged air-leak) or a significant delay of surgery. The doses-schedule escalation cohorts were (i) single pembro dose 3 wk prior to surgery; (ii) 2 pembro doses, 2 wks later surgery; (iii) 2 pembro doses, 1 wk later surgery. Expansion cohort received the doses-schedule of cohort (iii). Percentages of remaining viable tumor in the post-Tx were assessed, 10% or less was considered amajor pathological response (MPR). IHC for pre-Tx PDL1 was done. Efficacy was evaluated for the patients who had received 2 doses of pembrolizumab. Results: No DLT occurred in the dose-schedule escalation cohorts. 10 patients received 2 cycles of neo-adjuvant pembrolizumab. 4 patients achieved a MPR (4/10 who received 2 cycles of pembro; 40%; 95% C.I. 16.7-68.8%). No correlation is seen between the levels of PDL1 pre-Tx and the pathologic response. Size of the tumor and N status was also not in any apparent correlation with MPR (data not shown). Interestingly, all of the MPR cases had a relatively long interval from 1st Tx till surgery. Clinical trial information: NCT02938624. Conclusions: Neo-adjuvant pembro is safe and feasible. A promising sign of efficacy is seen. Achieving MPR might require a longer 1st-Tx-surgery interval. Predictive biomarkers for response might be different from those in advanced disease. Recruitment and correlative studies are ongoing.[Table: see text]

Precision medicine focuses on DNA abnormalities, but not all tumors have tractable genomic alterations. The WINTHER trial ( NCT01856296 ) navigated patients to therapy on the basis of fresh biopsy-derived DNA sequencing (arm A; 236 gene panel) or RNA expression (arm B; comparing tumor to normal). The clinical management committee (investigators from five countries) recommended therapies, prioritizing genomic matches; physicians determined the therapy given. Matching scores were calculated post-hoc for each patient, according to drugs received: for DNA, the number of alterations matched divided by the total alteration number; for RNA, expression-matched drug ranks. Overall, 303 patients consented; 107 (35%; 69 in arm A and 38 in arm B) were evaluable for therapy. The median number of previous therapies was three. The most common diagnoses were colon, head and neck, and lung cancers. Among the 107 patients, the rate of stable disease ≥6 months and partial or complete response was 26.2% (arm A: 23.2%; arm B: 31.6% (P = 0.37)). The patient proportion with WINTHER versus previous therapy progression-free survival ratio of >1.5 was 22.4%, which did not meet the pre-specified primary end point. Fewer previous therapies, better performance status and higher matching score correlated with longer progression-free survival (all P < 0.05, multivariate). Our study shows that genomic and transcriptomic profiling are both useful for improving therapy recommendations and patient outcome, and expands personalized cancer treatment. Prospective analysis of transcriptomic and genomic alterations increases the proportion of patients with solid cancer who are eligible for receiving matched therapies and shows promise in improving clinical outcomes.

297 Background: The subtype of pancreatic ductal adenocarcinoma cancer (PDAC) patients with DNA damage repair (DDR) deficiency from BRCA1/2 mutations has a favorable prognosis and is sensitive to platinum analogues and PARP inhibition. About 10-20% of PDAC patients have DDR deficiency without BRCA mutations (BRCA ness). The efficacy of olaparib in this population is unknown. Methods: Two parallel phases II trials (Israel and U.S.) are ongoing to determine the efficacy of olaparib in advanced PDAC with BRCA ness. Inclusion criteria: ≥ 1 prior systemic therapy for advanced PDAC, ECOG 0-1, germline BRCA 1/ 2 ( gBRCA) mutation negative, previously known DDR genetic aberrations (DDR-GA), family history of BRCA-associated cancers in ≥2 first-degree relatives (without DDR-GA), ATM loss by IHC (Israel only). Primary and secondary endpoints are objective response rate and PFS, respectively. With an type I error rate α of 0.1 and a β error rate of 0.2, and assuming P0 and P1 are 5% and 20%, respectively, study will enroll 24 patients at each site. Results: Thus far, 21 and 11 patients treated in Israel and U.S; respectively. DDR phenotype: Family history of BRCA cancer without DDR-GA (n = 14), DDR-GA (n = 12), ATM loss by IHC (n = 5). DDR-GAs were ATM (n = 6), PALB2 (n = 1), BRCA somatic (2), FANCB (1), PTEN (1) and CCNE1 (1). Efficacy data are in Table. Common toxicities were grade 1-2 anemia, fatigue and nausea. No responses were observed in platinum refractory cases. Conclusions: Olaparib was tolerated well in this study population. Olaparib showed encouraging initial antitumor activity in platinum-sensitive, gBRCA negative PDAC patients with DDR GA and in patients with family history of BRCA cancers (without identifiable DDR-GA). Clinical trial information: NCT02677038 ; NCT02511223. [Table: see text]

12011 Background: Precision medicine has focused mainly on matching drugs to tumor DNA alterations. However, not all individuals have tractable genomic alterations.We initiated the WINTHER trial to navigate patients to therapy based on either next generation sequencing (NGS) or transcriptomic analysis that compared tumor to normal tissue. Methods: Genomics (Arm A) was performed by NGS (N = 236 genes) (Foundation Medicine); transcriptomics (Arm B), by Agilent oligo-arrays (from fresh biopsies). A matching score was calculated for each patient (based on drugs received): for Arm A, number of alterations matched/total number of alterations; for RNA, by adding the reciprocals of the ranks of expression-matched drugs (using a transcriptomic algorithm). The clinical management committee (CMC) (lead investigators from the participating centers in 5 countries) suggested therapies, prioritizing genomic matches if available. The treating physician determined therapy given. Results: Overall, 303 patients consented; 107 (35%) received therapy consistent with CMC recommendations: 69 patients (64.5%) on Arm A (DNA-guided); 38 (35.5%), Arm B (RNA-guided). The median number of prior therapies was 3; median age = 59; median performance status = 1 (did not differ between arms). The most common diagnoses were colon, head/neck, and lung cancers. Adverse events after biopsy occurred in 1.2% of patients (1, (unrelated) convulsion; 2, pneumothorax). The rate of stable disease (SD) ≥ 6 months plus partial and complete response was 26.2%: Arm A, 23.2%; Arm B, 31.6%. Median progression-free survival (PFS) was 2.1 months (Arm A, 1.9; Arm B, 2.4). In multivariate analysis (hazard ratio (HR), 95% confidence interval (CI)), fewer prior therapies (0.63, 0.40-1.00, p = 0.048), better performance status (0.59, 0.37-0.92, p = 0.020) and a higher matching score (0.52, 0.33-0.82, p = 0.005) correlated with PFS. Higher matching score was also significantly associated with better overall survival (OS). (p = 0.012). Conclusions: Genomic and transcriptomic analysis were both useful for therapy selection. Higher degrees of DNA and RNA matching independently associated with longer PFS and OS. Clinical trial information: NCT01856296.

TPS11625 Background: Today, personalized cancer medicine implies matching the patient’s tumor genomic characteristics with molecularly and immune targeted agents. Although there are an increasing number of DNA aberrations that can now be matched to a cognate therapy, some patients do not display such druggable oncogene drivers. Methods: WINTHER is an open non-randomized study involving 6 cancer centers in France, Spain, Israel, Canada and USA applying genomic and also transcriptomic assays to guide treatment decisions. The novelty of the WINTHER approach lies in the use of tumor and matched normal tissue biopsies together and an algorithm for predicting efficacy of therapies. The aim is to provide a rational therapeutic choice for all of the patients enrolled in the study whether or not they harbor actionable DNA alterations. The study endpoint is the comparison of the progression-free-survival (PFS) under the WINTHER selected therapy to the PFS of the last therapeutic line. Patients included have refractory metastatic cancer of any histological type, with at least one prior therapeutic regimen and performance status of 0 to 1. Patients who have received a matched treatment based on a molecular anomaly as their immediate prior therapy were excluded. After consent, patients undergo a tumor and histologically-matched normal tissue biopsy. Extracted DNA and RNA of both tumor and normal from frozen tissues at the local center under common standard operating procedures are sent to centralized laboratories for omics investigations. DNA is investigated at Foundation Medicine Inc. and RNA at Gustave Roussy using Agilent technology. For RNA, the WINTHER algorithm is applied on the differential RNA expression data between tumor and normal tissues and establishes the list of drugs with the presumed higher score of efficacy for each patient. Patients with actionable genomic events enter in ARM A, and patients without any druggable anomaly of the DNA enter in ARM B and are treated using the WINTHER algorithm RNA-based treatment decision tool. To date, the trial has recruited 303 patients. Clinical trial information: NCT01856296.

Patient-tailored therapy based on tumor genomics is a promising tool in cancer therapy. However, in current practice it is limited to 30-40% of the patients whose tumor harbor actionable DNA mutations or amplifications. WINTHER is an open label non-randomized clinical trial developed by the WIN consortium to provide a rational personalized therapeutic choice to all (100 %) enrolled patients, irrespective of the type of genomic events. The study includes patients with metastatic cancer who progressed on at least one line of therapy. Matched tumor and normal tissue biopsies are collected from each patient and analyzed by next-generation-sequencing for known oncogenic driver aberrations (Foundation Medicine) or by functional genomics utilizing a prediction model of efficacy developed at Ben Gurion University. Based on these results study leaders from all centers make therapy decisions. The study aim is to compare progression free survival rates between the previous treatment line and the study drug/s. Patient accrual began in 2013 in four international cancer centers. The following is a description of the experience at Sheba Medical Center, specifically focusing on a large sub-population of lung cancer patients. Fifty six patients were screened and biopsied for the study. The majority of patients were diagnosed with lung cancers (52%), with a diverse representation of other malignancies including breast (16%), renal (9%), colon (9%), sarcoma, bladder and head and neck. Successful biopsies yielding sufficient material for genomic analyses were achieved in 35 subjects (63%). Lung biopsy success rates were 75% and 60% respectively for normal and tumor specimens. To date, 11 lung cancer patients were treated with a variety of chemotherapy (1) or biologic agents (11) based on study recommendations while 3 have yet to progress on previous therapy. Targeted genomic alterations included EGFR (3), RET (2), KRAS (2), ALK (1), ErbB2 (1), ErbB3 (1), BRAF (1). We observed a clinical benefit rate (CBR) of 55% (6/11) with 1 subject achieving compete response (CR), 2 partial responses (PR) and 3 stable disease (SD). Subjects recruited during the second year of the study, compared to the first year had a reduced biopsy failure rate, were more likely to receive treatment and achieved an increased clinical benefit. The proposed strategy for tumor genomic analysis based on the comparison of matched tumor and normal biopsies is acceptable and feasible. The experience of the multidisciplinary team is an important contributor to the program's success.

In the past decade, the oncology community has witnessed major advances in the understanding of cancer biology and major breakthroughs in several different therapeutic areas, from solid tumors to hematological malignancies; moreover, the advent of effective immunotherapy approaches, such as immune-checkpoint blockade, is revolutionizing treatment algorithms in almost all oncology disease areas. As knowledge evolves and new weapons emerge in the "war against cancer", clinical and translational research need to adapt to a rapidly changing environment to effectively translate novel concepts into sustainable and accessible therapeutic options for cancer patients.With this in mind, translational cancer researchers, oncology professionals, treatment experts, CRO and industry leaders, as well as patient representatives gathered in London, 16-17 March 2017, for The International Congress on Clinical Trials in Oncology and Hemato-Oncology (ICTO2017), to discuss the changing face of oncology clinical trials in the new era of personalized medicine and immuno-oncology. A wide range of topics, including clinical trial design in immuno-oncology, biomarker-oriented drug development paths, statistical design and endpoint selection, challenges in the design and conduct of personalized medicine clinical trials, risk-based monitoring, financing and reimbursement, as well as best operational practices, were discussed in an open, highly interactive format, favoring networking among all relevant stakeholders. The most relevant data, approaches and issues emerged and discussed during the conference are summarized in this report.

Abstract Scientific background: Activated macrophages, present in excess during natural inflammatory responses, bear the potential to kill and eradicate cancer cells. Efranat has developed cancer immunotherapy based on macrophage activation using a plasma protein designated EF-022, a modified Vitamin D Binding Protein Macrophage Activator. Methods: We performed an open label single-center phase I study in patients diagnosed with inoperable, recurrent or metastatic malignant solid tumors, deemed incurable, and who have failed to respond to standard therapy or for whom no standard therapy is available. The dose-escalation study was comprised of three cohorts, each receiving intramuscular (IM) injections of EF-022, once weekly for two cycles of treatment. Each cycle consisted of 4 weekly injections. Three dose levels were evaluated: 100 ng, 500ng and 1000ng. Patients were followed for up to 12 months from the start of treatment. The primary study objectives were to determine the safety and tolerability and to define the dose-limiting toxicities (DLT) and maximum tolerated doses (MTD). Blood and tissue biopsies were obtained for pharmacodynamics evaluation. Results: 12 patients with solid tumors have been enrolled. Median age = 65; male: female = 5:7. Among 12 treated patients, the most frequent drug related adverse events were flu like symptoms and rash and were mostly grade 1 or 2; no serious adverse events (SAE) related to study drug were observed. No DLTs were observed. CT imaging performed at 8 weeks showed stable disease (SD) in 5/12 patients (cholangiocarcinoma, H&N cancer, esophageal-gastric cancer, ovarian cancer and liposarcoma). 11 patients completed 57 days of treatment and 1 patient left the study after 1st cycle of treatment (29 days). Significant reduction in Tregs (CD4+CD127-CD25+) levels and increase in M1/M2 monocyte (CD14+HLA+ /CD16+CD163+) ratio in the blood was detected in most of the patients. In patients demonstrating SD an increase in the M1/M2 macrophage ratio (CD68+CD163-/ CD68+CD163+) was found at the tumor site. Conclusions: Treatment with EF-022 has an acceptable safety profile and resulted in disease stabilization in 42% of patients. Pharmacodynamics markers suggest a reduction of Tregs and increase of the M1/M2 ratio. These findings are being further explored in a dose expansion cohort. ClinicalTrials.gov Identifier: NCT02052492 Citation Format: Talia Golan, Raanan Berger, Aliza Ackerstein, Steve Raskin, Alexander M. Lesokhin, David Sidransky, Mark L. Levitt, Hana Gadassi, Uri Yogev, Michal Shahar. A phase 1 open label, dose-escalation trial evaluating the safety and tolerability of EF-022, macrophage activator, in subjects with advanced solid malignancies. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B30.

We have earlier shown an advantage in overall survival for malignant lymphoma (ML) patients who received combined Interleukin- 2 (rIL-2) and interferon alpha (IFN-alpha) immunotherapy after autologous stem cell transplantation (AutoSCT) in comparison with historic controls. On the basis of these results, we initiated a control prospective randomized multicenter 2-arm study, comparing the same combined immunotherapy treatment versus control for patients with malignant lymphoma after AutoSCT. One hundred nine patients were included in this study. After AutoSCT, patients were randomized either to the treatment group or to the control group. Patients in the treatment group received daily subcutaneous injections of rIL-2 6 x 10(6) IU/m(2)/d for 5 consecutive days followed by 2-weeks rest period. Subsequently, they were treated daily with rIL-2 6 x 10(6) IU/m(2)/d combined with INF-alpha 3 x 10(6) U/d for 5 consecutive days per week for 4 consecutive weeks. After 4 weeks of rest, IFN-alpha 3 x 10(6) U was administered for the next 6 months 3 times per week. Patients in the control group were followed up at the outpatient clinic. There was a significant enhancement of survival (P=0.05) and a clear trend in disease-free survival in favor of NHL patients receiving post-AutoSCT immunotherapy, in comparison with the control group. Eighty-nine percent of patients with NHL treated with immunotherapy were alive and 64% were disease free. In the control group, 66% of patients survived and 46% were disease free. Among the HL patients no significant differences were observed regarding survival, disease-free survival, and relapse rate. No serious toxicity events were observed. These results suggest that outpatient administered immunotherapy with IFN-alpha and rIL-2 is relatively well tolerated and may intensify remission in NHL patients, but not HL patients after AutoSCT.

2510 Background: Feasibility and safety of immunotherapy mediated by intentionally mismatched rIL-2 activated killer lymphocytes (IMAK) with no prior stem cells engraftment was investigated in pati...

The major cause of treatment failure following high-dose therapy with autologous stem cell transplantation (ASCT) for aggressive B cell non-Hodgkin's lymphoma (NHL) is persistent disease or recurrence. We describe our experience with the administration of rituximab post-ASCT, either as maintenance therapy or for the treatment of relapsed disease in patients with aggressive B cell NHL. Fifty-six patients achieved complete remission post-transplant, and 19 of them received maintenance with rituximab. Maintenance with rituximab resulted in statistically significant superior outcome in terms of progression free (PFS; p = 0.002) and overall survival (OS; p = 0.011). The median PFS and OS of patients in the maintenance arm has not been reached yet, while the median PFS and OS of patients in the control arm were 29 and 42 months, respectively. Fifty-four patients had disease progression or relapsed post-ASCT, and 15 of them received rituximab in combination with chemo- and/or radiotherapy in order to achieve disease remission. Therapeutic administration of rituximab resulted in statistically significant prolongation of OS (p = 0.021). The median OS of patients treated with rituximab was 17 months, while median OS of patients in the control group was 10 months. We consider that the results of our study are promising but need to be verified within large randomized trials.

The influence of graft composition on the outcome of reduced-intensity (RIC) allogeneic PBSC transplantation (allo-PBSC) remains controversial. In this study, we analyzed the impact of CD34+ cell dose on the incidence of GVHD, and on the outcome after allo-PBSC, in 103 patients with hematological malignancies, using a uniform RIC regimen. The following variables were included in statistical analysis: (1) number of C34+ cells, (2) high-risk vs low-risk disease status, (3) matched related vs matched unrelated donor, (4) female donor to male recipient vs any other combination, (5) age of recipient (above vs below the median). Univariate and multivariate analysis did not reveal any association between CD34+ cell dose and acute grade-2 to grade-4, cGVHD, non-relapse mortality (NRM), relapse rate (RR) and OS. High-risk disease status was the only variable independently associated with increased NRM (P=0.001), increased RR (P=0.012) and decreased OS (P<0.001). The same results were obtained when analysis was restricted to a subgroup of 55 patients with myeloid neoplasms. The influence of graft composition on the outcome of RIC allo-PBSC should be further investigated via well-controlled randomized prospective studies.

The effect of ABO-incompatibility on transplantation outcome remains a controversial issue, with many of the reported studies showing conflicting results. In this study, we evaluate: the association between ABO-incompatibility and myeloid engraftment; the incidence and severity of acute and chronic graft-versus-host disease (GVHD); non-relapse mortality (NRM); GVHD-associated mortality, relapse and overall survival (OS). Our study includes 221 patients with malignant diseases treated in the same institution with the same reduced intensity regimen. Other variables known to affect the transplantation outcome such as age, disease, disease risk, and donor characteristics were well-balanced between ABO-matched and ABO-mismatched transplants. Analysis of our data shows increased incidence of NRM during the first months after transplantation in the groups of patients with major and minor ABO-incompatibility. Although neither incidence nor severity of GVHD differed significantly among the different groups, we found increased mortality associated with GVHD in the major ABO-incompatible groups. Long-term OS and relapse rate were not different, although we observed a trend for decreased OS during the first year post transplantation in the group of patients with major ABO-incompatibility. Our study showed that ABO-incompatibility has an adverse impact on the transplantation outcome.