Clinical Trials of Cancer Immunotherapies最新文献

{"title":"Abstract A002: Autologous Tcells transduced with the affinity enhanced NY-ESO-1c259TCR in patients with synovial sarcoma expressing low levels of the NY-ESO-1 antigen","authors":"D. Araujo, S. D’Angelo, G. Demetri, M. Druta, J. Glod, W. Chow, W. Tap, J. Senra, R. Abbott, E. V. Winkle, K. Chagin, M. Maroto, E. Norry, M. Iyengar, T. Trivedi, A. Gerry, R. Amado, C. Mackall","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A002","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A002","url":null,"abstract":"Background: NY-ESO-1c259 is an affinity optimized TCR recognizing an NY-ESO-1-derived peptide complexed with HLA-A*02 (SPEAR T-cells). NY-ESO-1c259TCR therapy induced responses in ~50% of patients whose tumors express high level NY-ESO-1 (NCT01343043). Here we report on preclinical studies of TCR activity and results from a cohort of patients whose tumors express low NY-ESO-1 levels. Methods: T-cell response against tumor-derived cell lines with differential NY-ESO-1 expression levels was assessed by ELISA. Patients had selected HLA subtypes (HLA-A*02:01, 02:05, 02:06) and advanced NY-ESO-1+ SS. In this cohort, tumors express NY-ESO-1 at ≥ 1+ in > 1% but 1×10e4 mRNA copies/10e6 reference gene transcripts. Ten patients in this cohort have been treated (as of 23Nov17). One died due to disease progression 2 days post infusion. Four have had a partial response (ORR 40%), and median duration of response was 8.5 weeks (range, 8-13). Antigen expression level by IHC (% 1+, 2+, and/or 3+), best overall response (BOR) by RECIST v1.1, and transduced cell expansion (copies/microgram DNA) are listed below for the 9 evaluable patients: Pt 264, 30% 1+/2+, PR, 86320; Pt 313, 90% 1+, PR, 45430; Pt 325, 10% 2+, PR, 13365; Pt 331, 40% 1+, 10% 2+, 10% 3+, PR, 197546; Pt 324, 50% 1+, 10% 2+, SD, 133334; Pt 305, 5% 1+, 5% 2+, 5% 3+, SD, 74855; Pt 322, 50% 1+, 10% 2+, SD, 54569; Pt 323, 20% 1+, 10% 2+, SD, 50912; Pt 211, 10% 1+, 20% 2+, 20% 3+, PD, 22627. Conclusions: In vitro assays can assess mRNA levels and protein expression of target antigen required for T-cell activation and cytotoxicity, predicting expression levels required for anti-tumor activity in vivo. The patient data suggest that affinity optimized TCRs can be used to treat tumors with low target antigen expression. Citation Format: Dejka Araujo, Sandra D9Angelo, George Demetri, Mihaela Druta, John Glod, Warren Chow, William Tap, Joana Senra, Rachel Abbott, Erin Van Winkle, Karen Chagin, Miguel Maroto, Elliot Norry, Malini Iyengar, Trupti Trivedi, Andrew Gerry, Rafael Amado, Crystal Mackall. Autologous Tcells transduced with the affinity enhanced NY-ESO-1c259TCR in patients with synovial sarcoma expressing low levels of the NY-ESO-1 antigen [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A002.","PeriodicalId":244081,"journal":{"name":"Clinical Trials of Cancer Immunotherapies","volume":"14 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"126003147","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract A012: SV-BR-1-GM, a whole-cell targeted immunotherapy for advanced breast cancer: Pharmacodynamic markers of response","authors":"M. Lacher, Sanne Graeve, V. Sunkari, D. Adams, Cha-Mei Tang, P. Amstutz, C. Wiseman, G. Peoples, W. Williams","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A012","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A012","url":null,"abstract":"Background: SV-BR-1-GM is a GM-CSF-engineered breast cancer cell line employed – after irradiation – as a targeted immunotherapy for advanced breast cancer. Tumor regressions at metastatic sites have been observed, most notably in patients with HLA allele matches to the cell line. We are assessing SV-BR-1-GM in the phase IIa portion of a phase I/IIa clinical trial in metastatic and locally recurrent breast cancer (ClinicalTrials.gov identifier NCT03066947). Additionally, we are co-developing a companion diagnostic (BriaDX™) to identify patients likely to respond to SV-BR-1-GM. Currently, BriaDX™ consists of HLA typing; however, we have begun assessing biomarkers in sera, lymphocyte characteristics, circulating tumor cells (CTCs), and cancer-associated macrophage-like cells (CAMLs) from patients collected at baseline and after inoculation of SV-BR-1-GM to layer in additional components to improve accuracy, with the number/subtyping of CTCs and CAMLs being prognostic indicators. Methods: Subjects are pretreated with low-dose cyclophosphamide to reduce immune suppression. SV-BR-1-GM is inoculated intradermally with follow-up local injections of IFNα2. Cycles are every 2 weeks x 3, then monthly. HLA typing was conducted via LabType R-SSO Kits (One Lambda). Cytokines were measured via single- or multiplex assays. Anti-SV-BR-1 antibodies were determined by incubation of SV-BR-1 cells with diluted patient sera followed by staining with a fluorescently-labeled anti-IgG antibody and detection by flow cytometry. CTCs and CAMLs were evaluated by CellSieve™ at Creatv MicroTech. Results: To date, 16 clinical trial subjects have been inoculated with the SV-BR-1-GM regimen as rescue immunotherapy. All were treatment refractory and had received a median of 4.5 prior chemo/biologic therapy regimens (range 1-13). Two of the 16 patients remained on study for ≥3 months (5 cycles) with 4 patients currently on study not having reached the 3-month evaluation time point. Objective regression of tumor was seen in 2 subjects. One subject had virtually complete regression of 20 of 20 lung metastases noted at 3 and 6 months (but with progressive bone and liver metastases). Another subject had improvement of chest wall metastases and quality of life but expired due to nontreatment-related causes. Response appeared to correlate with HLA allele-matching to SV-BR-1-GM. Anti-SV-BR-1 antibody titers increased in several patients. Among the cytokines assessed, interleukin (IL)-8 levels increased in HLA-DRB3 allele-matched subjects after SV-BR-1-GM inoculation. Of 15 patients evaluated, CTCs were present in 6 patients at baseline while CAMLs were present in all 15. Five of 5 patients evaluated for PD-L1 expression had mostly low-to-medium expression of PD-L1 on their CTCs/CAMLs. In the patient who had regression of lung metastases but progression of liver metastases, PD-L1 expression and maximum CAML size increased, but the number of CAMLs decreased during treatment. CAML number al","PeriodicalId":244081,"journal":{"name":"Clinical Trials of Cancer Immunotherapies","volume":"394 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"133522743","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract A005: A phase I study of the safety and immunogenicity of a multipeptide personalized genomic vaccine in the adjuvant treatment of solid cancers","authors":"A. Blázquez, A. Rubinsteyn, Julia Kodysh, J. Finnigan, T. Marron, R. Sabado, M. Meseck, Tim O’Donnell, Jeff Hammerbacher, M. Donovan, J. Holt, M. Mahajan, J. Mandeli, K. Misiukiewicz, E. Genden, Brett A. Milles, H. Khorasani, P. Dottino, H. Irie, A. Tiersten, E. Port, A. Wolf, He-Jin Cho, A. Tewari, S. Parekh, S. Nair, M. Galsky, W. Oh, S. Gnjatic, E. Schadt, P. Friedlander, N. Bhardwaj","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A005","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A005","url":null,"abstract":"Introduction: Mutation-derived tumor antigens (MTAs) arise as a direct result of somatic variations, including nucleotide substitutions, insertions, and deletions that occur during carcinogenesis. These somatic variations can be characterized via genetic sequencing and used to identify MTAs. We developed a platform for a fully-personalized MTA-based vaccine in the adjuvant treatment of solid and hematologic malignanicies. Methods: This is a single-arm, open label, proof-of-concept phase I study designed to test the safety and immunogenicity of Personalized Genomic Vaccine 001 (PGV001) that targets up to 10 predicted personal tumor neoantigens. The single-center study will enroll 20 eligible subjects with histologic diagnosis of solid and hematologic malignancies. Subjects must have no measurable disease at time of first vaccine administration, and 5-year disease recurrence risk of > 30%. Toxicity will be defined by CTCAE v5.0. Blood samples will be collected at various time points for immune response monitoring. Each patient’s vaccine peptides are selected by identifying somatic mutations from comparison of tumor and normal exome sequencing data, phasing somatic variants with co-occurring germline variants using tumor RNA sequencing data, and ranking mutated peptide sequences ”Openvax pipeline.” The process for determining somatic variants hews closely to the Broad Institute’s “Best Practices” for cancer SNVs and indels. The phasing of somatic and germline variants is implemented in a custom bioinformatics tool called Isovar. Mutated protein sequences containing phased variants are ranked according to two criteria: expression of the mutant allele in tumor RNA and aggregated predicted affinity to the patient’s Class I MHCs. Both quantities are normalized and multiplied together to create single ranked ordering of the candidate mutant sequences. Results: PGV001_002 (head and neck squamous cell cancer), who has completed vaccination, received 10 doses of vaccine comprising 10 long peptides (25 amino acid length) combined with poly-ICLC (toll-like receptor-3 agonist) intradermally. Vaccine-induced blood T-cell responses were determined, at weeks 0 (before-treatment) and 27 (after-treatment), ex vivo by interferon (IFN)-g enzyme-linked immunospot (ELISPOT) assay and after in vitro expansion by intracellular cytokine staining (ICS). Overlapping 15-16-mer assays peptides (OLPs) spanning the entirety of each ILP and 9-10-mer peptides corresponding to each predicted class I epitope (Min) were pooled and used to monitor immunogenicity. Ex vivo responses to these peptide pools were undetectable at week 0 but were evident at week 27 against 2 OLPs out of 10 (20%) and in 5 Min out of 10 (50%). After in vitro expansion, neoantigen-specific CD4+ and CD8+ T-cell responses were found in 5 out of 10 pooled peptides (50%). 7 out of 10 (70%) epitopes elicited polyfunctional T-cell responses (secretion of INF-α, TNF-α, and/or IL-2) from either CD4+ or CD8+ T-cells. C","PeriodicalId":244081,"journal":{"name":"Clinical Trials of Cancer Immunotherapies","volume":"253 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"132601229","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract A014: Phase I clinical trial with PD-1/MUC1 CAR-pNK92 immunotherapy","authors":"Qiao Li, Yi Wang, Ming Lin, Leiming Xia, Yangyi Bao, Xiangle Sun, Lin Yang","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A014","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A014","url":null,"abstract":"Mucin1 (MUC1) proteins represent a family of high molecular weight trans-membrane glycoproteins that protect epithelial cells and mediate signal transduction by communication with extracellular stimuli. On the other hand, MUC1 has been observed to be overexpressed and glycosylated in adenocarcinoma, making it an ideal molecular target for cancer treatment. MUC1 based antibody and specific chimeric antigen receptors (CARs) modified T/NK cells exhibit strong antibody-dependent or direct-cell cytotoxicity to MUC1 positive tumor cells. However, treatment failure with MUC1-targeted therapy was usually caused by tumor microenvironment (TME)-driven immune suppression. PD-L1 has been identified as a negative checkpoint molecule that promotes immune evasion of tumor cells. The interaction of PD-1 and PD-L1 inhibits the function of tumor-infiltrating lymphocytes (TILs) or infused T/NK cells while activating the negative immune-regulatory cells in TME, such as regulatory T-cells and MDSCs. To overcome these barriers, we engineered clinically applicable NK-92 cells by lentiviral gene transfer to express chimeric antigen receptors comprising an anti-MUC1 scFv antibody fusion protein with CD28-CD137 as a signaling moiety and truncated PD-1 peptide. NK92 cells expressing anti-MUC1 CAR specifically and efficiently lysed MUC1 positive tumor cells in vitro and in vivo. The safety of NK-92 cell administration has been demonstrated by numerous phase I clinical trials. In our study, 13 patients with different kinds of tumors (lung cancer, pancreatic cancer, colon cancer and ovarian cancer) with positive PD-L1 and MUC-1 expression were enrolled. CAR-NK cells were infused (1×109 cells/time) into these patients. Of 13 patients, 3 patients were withdrawn, 9 patients (69.2%) showed stable disease and 1 patient showed progressive disease. The cytokine level and hematologic changes were monitored to evaluate the safety. Severe cytokine storm and/or bone marrow suppression were not observed. From this phase I clinical trial we found that CAR-NK therapy has a broad prospect of application as a new cellular immunotherapy due to its stable clinical efficacy, mild side effects and ease of preparation. Citation Format: Qiao Li, Yi Wang, Ming Lin, Leiming Xia, Yangyi Bao, Xiang Sun, Lin Yang. Phase I clinical trial with PD-1/MUC1 CAR-pNK92 immunotherapy [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A014.","PeriodicalId":244081,"journal":{"name":"Clinical Trials of Cancer Immunotherapies","volume":"18 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"126067303","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract A011: First-in-man clinical trial of intratumoral injection of Clostridiumnovyi-NT spores in patients with treatment-refractory advanced solid tumors: Safety, activity, and immune responses","authors":"F. Janku, M. Gounder, A. Pezeshki, R. Murthy, A. Wang-Gillam, D. Shepard, D. Hong, S. Piha-Paul, Anjali Raina, A. Leontovich, G. Decrescenzo, B. Kreider, David Tung, M. Varterasian, H. Zhang, K. Khazaie","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A011","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A011","url":null,"abstract":"Bacteriolytic strategies offer unique advantages to combat a broad range of cancers often refractive to conventional chemotherapies and/or radiotherapies. C. novyi-NT is an attenuated strain of Clostridium novyi, a spore-forming, gram-positive, obligate anaerobe that lacks a lethal alpha- toxin, expressed by the parental strain. When administered intravenously or intratumorally with percutaneous injection, C. novyi-NT colonizes and replicates within the hypoxic region of the tumors, eliciting robust, tumor-confined cell lysis. In this first-in-man phase 1 study, patients with injectable treatment-refractory solid tumors received a single intratumoral injection of C. novyi-NT spores across 6 dose cohorts (spore concentrations of 104, 3x104, 105, 3x105, 106, 3x106) using a 3+3 trial design. The primary endpoints were to assess the safety profile, the dose limiting toxicity, and the maximum tolerated dose of C. novyi-NT. Key secondary endpoints included assessments of the preliminary antitumor activity of the injected tumor, an overall response evaluated by RECIST v. 1.1, and the host immune and inflammatory response to C. novyi-NT. Twenty-four patients were enrolled between November, 2013 and April, 2017. A single intratumoral injection of C. novyi-NT led to germination and resultant tumor lysis of injected tumor masses in 46% of patients across all dosing cohorts. The cohort 5 dose of 106 spores was defined as the maximum tolerated dose. Dose-limiting toxicities were grade 4 sepsis and grade 4 gas gangrene (n=1), all in patients with germination. In the 22 evaluable patients, 21 (95%) had stable disease (SD) as the best response for the injected lesion (tumor shrinkage of > 10% was observed in 21% of patients) and 19 (86%) had overall SD as the best response per RECIST 1.1. C. novyi-NT injection resulted in transient serum cytokine responses consistent with inflammasome activity, activation of innate immunity, tissue remodeling, and angiogenesis. Tumor antigen specific ELISPOT assays pre- and post- treatment documented enhanced secretion of IFNγ and TNFα by circulating T-cells, indicating improved systemic tumor specific T-cell responses. Multiparametric in situ immunostaining of core biopsies suggested improved immune cell infiltration in metastatic lesions. These early signs of improved antitumor activity in patients with advanced solid tumors have encouraged a new trial of C. novyi-NT in combination with immune checkpoint inhibitors. Citation Format: Filip Janku, Mrinal Gounder, Abdul Mohammad Pezeshki, Ravi Murthy, Andrea Wang-Gillam, Dale Shepard, David S. Hong, Sarina A. Piha-Paul, Anjali Raina, Alexey A. Leontovich, Gary DeCrescenzo, Brent L. Kreider, David Tung, Mary Varterasian, Halle H. Zhang, Khashayarsha Khazaie. First-in-man clinical trial of intratumoral injection of Clostridiumnovyi-NT spores in patients with treatment-refractory advanced solid tumors: Safety, activity, and immune responses [abstract]. In: Proceedings of the Fourth ","PeriodicalId":244081,"journal":{"name":"Clinical Trials of Cancer Immunotherapies","volume":"1 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"127023887","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract A008: Neoadjuvant nivolumab, gemcitabine and cisplatin in muscle-invasive bladder cancer: Study update","authors":"Shilpa Gupta, C. Weight, N. Agarwal, Sumati V Gupta, B. Konety, E. Gibb, E. Davicioni, B. Thyagarajan, G. Sonpavde","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A008","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A008","url":null,"abstract":"Background: Cisplatin-based neoadjuvant chemotherapy in muscle-invasive bladder cancer (MIBC) improves survival which correlates with pathologic response (PaR) at radical cystectomy (RC). Immunotherapy with checkpoint inhibitors has improved outcomes in advanced bladder cancer and immunotherapy is synergistic with chemotherapy. Our ongoing trial is aimed at studying the efficacy and safety of nivolumab (N)with gemcitabine-cisplatin (GC) as neoadjuvant therapy for MIBC (NCT03294304). Methods: This is a single-arm, multicenter phase II study for patients with MIBC eligible for neoadjuvant GC and planned for RC. Forty-one patients will be treated with N+ GC every 21 days for 4 treatment cycles over 12 weeks followed by RC. The primary endpoint is PaR. Key inclusion criteria are presence of MIBC (predominantly urothelial carcinoma) with clinical stage T2-T4a and N≤1 disease (solitary lymph node measuring Citation Format: Shilpa Gupta, Christopher J. Weight, Neeraj Agarwal, Sumati Gupta, Badrinath Konety, Ewan Gibb, Elai Davicioni, Bharat Thyagarajan, Guru Sonpavde. Neoadjuvant nivolumab, gemcitabine and cisplatin in muscle-invasive bladder cancer: Study update [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A008.","PeriodicalId":244081,"journal":{"name":"Clinical Trials of Cancer Immunotherapies","volume":"42 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"122645586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract A007: Comparison of pretreatment conditioning on efficacy in two cohorts of a pilot study of genetically engineered NY-ESO-1c259T-cells in patients with synovial sarcoma","authors":"S. D’Angelo, D. Araujo, B. A. Tine, G. Demetri, M. Dutra, J. Glod, W. Chow, S. Grupp, Alibiruni Abdul Razak, W. Tap, B. Wilky, E. V. Winkle, E. Norry, Samik Basu, K. Chagin, M. Iyengar, T. Trivedi, R. Amado, C. Mackall","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A007","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A007","url":null,"abstract":"Background: NY-ESO-1c259T-cells recognizing an NY-ESO-1 derived peptide complexed with HLA-A*02 (SPEAR T-cells) are being studied in an ongoing multi-cohort clinical trial in synovial sarcoma (NCT01343043). We compared safety, efficacy and cell persistence between two cohorts using different doses of lymphodepleting chemotherapy. Methods: There are four cohorts separated by differing antigen expression levels and lymphodepletion regimens, and this assessment compares cohorts 1 (closed) and 4 (ongoing). In both, ≥50% patient tumor cells expressed NY-ESO-1 at 2+/3+ levels by immunohistochemistry. Following apheresis, T-cells are isolated, activated, transduced to express NY-ESO-1c259T and expanded. Lymphodepletion in cohort 1 consists of fludarabine 30 mg/m2/d × 4 d and cyclophosphamide 1800 mg/m2/d × 2d, and in cohort 4 consists of fludarabine 30 mg/m2/d × 3d and cyclophosphamide 600 mg/m2/d × 3d. Target dose is 1–6 × 109 transduced cells. Disease is assessed at weeks 4, 8 and 12 and every 3 months until disease progression. Results: 12 patients were treated in cohort 1 and 14 patients in cohort 4 (as of 23Nov17). Median transduced cell dose was 3.6 × 109 cells in cohort 1 and 2.6 × 109 cells in cohort 4. Treatment-related adverse events (AEs) were observed in 100% of patients in cohort 1 and 86% in cohort 4; related serious adverse events (SAEs) were reported in 50% of cohort 1 and 14% of cohort 4. There were no fatal AEs. Overall response rate (ORR) in cohort 4 is 29% vs 50% in cohort 1, and duration of response is in cohort 4 is 16 weeks vs 31 weeks in cohort 1. The best overall response of stable is 50% in cohort 1 and 64% in cohort 4. Median peak expansion of transduced T-cells in peripheral blood in responders is lower in cohort 4 (40,137 copies/μg DNA) vs cohort 1 (106,174 copies/μg DNA). Median absolute lymphocyte counts following lymphodepletion were 1×107/L (range 0-3) in cohort 1 and 9×107/L (0-40) in cohort 4. Conclusions: The greater ORR and higher peak expansion in cohort 1 may be attributable to the dose intensity of the lymphodepleting regimen. Although related SAEs were reported in a higher proportion in cohort 1 than 4, the safety and tolerability are acceptable in both, and cell doses were similar. The data and overall benefit:risk considerations support utilizing higher doses of preconditioning chemotherapy in future trials. Citation Format: Sandra P. D9Angelo, Dejka Araujo, Brian Van Tine, George Demetri, Mihaela Dutra, John Glod, Warren Chow, Stephen Grupp, Alibiruni Abdul Razak, William Tap, Breelyn Wilky, Erin Van Winkle, Elliott Norry, Samik Basu, Karen Chagin, Malini Iyengar, Trupti Trivedi, Rafael Amado, Crystal Mackall. Comparison of pretreatment conditioning on efficacy in two cohorts of a pilot study of genetically engineered NY-ESO-1c259T-cells in patients with synovial sarcoma [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival","PeriodicalId":244081,"journal":{"name":"Clinical Trials of Cancer Immunotherapies","volume":"78 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"126297518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract A017: Immunologic efficacy of heat shock protein 105 peptide vaccine in patients with advanced colorectal and esophageal cancer","authors":"Yasuhiro Shimizu, T. Yoshikawa, Kojima Takashi, K. Shoda, Kazuto Nosaka, S. Mizuno, S. Wada, Yuki Fujimoto, T. Sasada, Kenichi Kohashi, H. Bando, I. Endo, T. Nakatsura","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A017","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A017","url":null,"abstract":"Purpose: Heat shock protein 105 (HSP105) is overexpressed in a variety of human cancers, including colorectal cancer (CRC) and esophageal cancer (EC). We identified HLA-A24 or A2-restricted HSP105 peptides that can induce HSP105 peptide-specific cytotoxic T lymphocytes (CTLs) (EP1536006, JP5112615, JP5291641, US9,404,925) and curried out a phase I clinical trial of HLA-A24 or A2-restricted HSP105 peptide vaccine in patients with CRC or EC (UMIN ID000017809). In this study, we aimed to demonstrate the immunological efficacy of the novel vaccine. Experimental design: 30 patients (HLA-A24 group; 15 patients, HLA-A2 group; 15 patients) with advanced CRC or EC were enrolled. Two types of vaccine (A24-1 and A24-7 or A2-7 and A2-12) were administered into the patients, matching HLA-types. Immunological responses were analyzed by ex vivo and in vitro IFN-γ ELISPOT assay using peripheral blood mononuclear cells before and after vaccination, and cytokines produced by HSP105-specific CTLs were measured by Cytometric Bead Array assay. We also analyzed the correlation between immunological responses and prognosis. Result: HSP105 peptide vaccines induced HSP105 peptide-specific CTLs in 15 of 30 patients. In HLA-A24 group, there were 7 patients with the induction only in ex vivo and almost all patients (n=13) showed skin reactions of vaccine sites. By contrast, in HLA-A2 group, there were 4 patients with the induction in ex vivo and 6 patients in in vitro, respectively, and only 6 patients with skin reactions of vaccine sites. In all patients, the existence of skin reaction correlated with the induction in ex vivo (p Citation Format: Yasuhiro Shimizu, Toshiaki Yoshikawa, Kojima Takashi, Kayoko Shoda, Kazuto Nosaka, Shoichi Mizuno, Satoshi Wada, Yuki Fujimoto, Tetsuro Sasada, Kenichi Kohashi, Hideaki Bando, Itaru Endo, Tetsuya Nakatsura. Immunologic efficacy of heat shock protein 105 peptide vaccine in patients with advanced colorectal and esophageal cancer [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A017.","PeriodicalId":244081,"journal":{"name":"Clinical Trials of Cancer Immunotherapies","volume":"91 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"122876533","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract A013: Haploidentical stem cell transplantation and subsequent immunotherapy with antiGD2 antibody for patients with relapsed metastatic neuroblastoma","authors":"P. Lang, Tim Flaadt, M. Ebinger, P. Schlegel, H. Lode, R. Ladenstein, Anne-Marie Lang, Peter Ambross, J. Schaefer, J. Fuchs, H. Loibner, W. Schwinger, R. Handgretinger","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A013","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A013","url":null,"abstract":"Background: Pediatric patients with relapsed metastatic neuroblastomas have a poor prognosis and additional strategies are needed. We present results of a phase I/II-trial with subsequent immunotherapy with an anti-GD2mAb (CH14.18/CHO) after HLA-mismatched, haploidentical stem cell transplantation (SCT). Methods: T- and B-cell depleted stem cells from parental donors were used in combination with melphalan 140mg/m², thiotepa 10mg/kg, fludarabin 160mg/m² and ATG-F. CH14.18/CHOmAb was started on day 60-180 post-transplant: 6 cycles with 20mg/m²/day x 5; in cycles 4-6, 1x10 6 U/m² Interleukin 2 was given additionally. Disease status was evaluated with whole body MRI, MIBG scan and MRD detection in bone marrow aspirates. Primary endpoint was success of treatment, defined as a patient receiving the full protocol treatment, still alive 180 days after end of treatment without progression/unacceptable toxicity or severe GvHD. Results: 56 patients with 1st or ≥2nd metastatic relapse were enrolled. Disease status prior to antibody infusions was: CR (n=19), PR (n=31), mixed (n=6). 41% of patients with measurable tumor burden responded and reached CR after treatment. 90% of patients with initial CR could maintain this status. In total, success of treatment was observed in 60%. 3-year OS and EFS was 58% and 45%, respectively. Causes of death were: progression/relapse (25%) or TRM (7%). Factors of influence on EFS were (1) remission status prior to SCT (with CR, PR or mixed response resulting in 70%, 45% and 11% 3yEFS) and (2) bone marrow involvement prior to CH14.18 treatment (no MRD detectable: 60% 3yEFS vs. any MRD detectable: 20% 3yEFS). Frequent side effects were pain, fever, CRP elevation; rare side effects comprised SIRS/capillary leak syndrome, seizures, accommodation disturbances. Transient acute severe GvHD occurred in 1 patient. Conclusions: CH14.18/CHO infusions after haploidentical SCT are feasible with acceptable toxicity. Our results suggest an antitumor effect of the new, donor-derived immune system in combination with CH14.18 treatment. Citation Format: Peter Lang, Tim Flaadt, Martin Ebinger, Patrick Schlegel, Holger Lode, Ruth Ladenstein, Anne-Marie Lang, Peter Ambross, Juergen Schaefer, Joerg Fuchs, Hans Loibner, Wolfgang Schwinger, Rupert Handgretinger. Haploidentical stem cell transplantation and subsequent immunotherapy with antiGD2 antibody for patients with relapsed metastatic neuroblastoma [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A013.","PeriodicalId":244081,"journal":{"name":"Clinical Trials of Cancer Immunotherapies","volume":"17 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"126386909","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract A018: Effects of Toca 511 and Toca FC on tumor microenvironment and peripheral blood populations in patients with advanced malignancies","authors":"J. Merchan, J. Rodón, Derek Ostertag, S. Venkat, A. Donahue, P. Horner, Dalissa Tijera, T. Kheoh, D. Jolly, H. Gruber, J. Shorr, G. Falchook","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-A018","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A018","url":null,"abstract":"Toca 511 (vocimagene amiretrorepvec) is an investigational, conditionally lytic, retroviral replicating vector that selectively infects cancer cells due to cell division requirements for virus integration into the genome, and defects in innate and adaptive immune responses found in malignant tissues that support virus replication. Toca 511 spreads through cancer cells and stably delivers optimized yeast cytosine deaminase (CD) that, upon administration of the prodrug, Toca FC (an investigational, extended-release version of 5-fluorocytosine [5-FC]), converts 5-FC into 5-fluorouracil (5-FU). 5-FU kills infected dividing cancer cells and diffuses to and kills surrounding cells in the tumor microenvironment, including immunosuppressive myeloid cells. In animal models, this depletion of immunosuppressive myeloid cells leads to therapeutically active immunity against tumors. A similarly derived antitumor response may occur in cancer patients, as local injection of Toca 511 into the tumor bed after resection of recurrent high-grade glioma followed by treatment with Toca FC has been associated with prolonged survival and durable complete responses (median duration of follow-up: 37.4+ months); responses were delayed in onset, consistent with time to response for immuno-oncology agents. The current phase 1b, multicenter, open-label study (Toca 6; NCT02576665) is designed to investigate changes in immune activity after treatment with Toca 511 and Toca FC in patients with advanced malignancies. Toca 511 is administered intravenously (IV) daily for 3 days and then as a single injection into metastatic or recurrent tumor. Oral Toca FC is started ~4 weeks later and repeated every 4-6 weeks. Biopsies are obtained prior to and following exposure to Toca 511 and Toca FC treatment to evaluate changes in immune activity, and peripheral blood is obtained contemporaneously for evaluation. The study has enrolled 19 patients to date (colorectal cancer: 15; sarcoma: 2; non-small cell lung and pancreas cancer: 1 each). Treatment has been well tolerated. Viral RNA, DNA, and CD protein expression are observed in tumor after IV delivery of Toca 511. We plan to report on tumor microenvironment remodeling that follows treatment with Toca 511 and Toca FC. Infiltrating T-cell subpopulations, B cells, and monocytes quantified by immunofluorescence from stained formalin-fixed, paraffin-embedded samples will be presented. Additionally, changes in peripheral blood, including T-cell effector, helper/memory, and regulatory populations, and myeloid lineage cells following exposure to Toca 511 alone and following subsequent exposure to Toca FC will be reported. Data from this study will inform future development of Toca 511 and Toca FC alone or in combination with other therapies in patients with solid tumors. Citation Format: Jaime Merchan, Jordi Rodon, Derek Ostertag, Shree Venkat, Arthur Donahue, Peder Horner, Dalissa Tijera, Thian Kheoh, Douglas J. Jolly, Harry E. Gruber, Jolene S.","PeriodicalId":244081,"journal":{"name":"Clinical Trials of Cancer Immunotherapies","volume":"12 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"131634411","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}