Antitumor Effects In Patients Research Articles

TRITON2: An international, multicenter, open-label, phase II study of the PARP inhibitor rucaparib in patients with metastatic castration-resistant prostate cancer (mCRPC) associated with homologous recombination deficiency (HRD).

TPS388 Background: Up to 25% of patients with advanced prostate cancer, including mCRPC, have a deleterious germline or somatic mutation in BRCA1, BRCA2, ATM or another homologous recombination (HR) DNA repair gene that can serve as a molecular marker to select those who may respond to poly(ADP-ribose) polymerase inhibitors (PARPis). PARPis are lethal to cells with HRD, and PARPi treatment has shown preliminary evidence of an antitumor effect in patients with mCRPC who harbor a mutation in an HR DNA repair gene (Mateo et al. N Engl J Med. 2015;373:1697-708). These data provide a compelling rationale for evaluating rucaparib, a potent PARP1, PARP2 and PARP3 inhibitor, in patients with mCRPC associated with HRD. Methods: TRITON2 (NCT02952534) is a phase 2 study evaluating rucaparib 600 mg BID in patients with mCRPC. Patients with a deleterious germline or somatic BRCA1, BRCA2 or ATM mutation (per prior local test or central test during screening) will be enrolled into 1 of 2 cohorts based on the presence or absence of measurable visceral and/or nodal disease. An exploratory cohort will enroll patients with an alteration in any of 12 other prespecified HR genes (eg, RAD51C, RAD51D and PALB2), with or without measurable visceral and/or nodal disease. Patients must have progressed on androgen receptor signaling–directed therapy and 1 prior taxane-based chemotherapy for mCRPC. Patients who received prior treatment with a PARPi, mitoxantrone, cyclophosphamide or platinum-based chemotherapy are excluded. The primary endpoint is objective response rate measured using modified RECIST v1.1/PCWG3 for patients with soft-tissue disease and prostate-specific antigen response for patients with nonmeasurable disease. Secondary endpoints include duration of response, radiographic progression-free survival, overall survival, clinical benefit rate and safety. Pretreatment blood samples collected from all patients will enable development of a plasma-based companion diagnostic to select patients who may benefit from rucaparib treatment. Patients (≈160) will be enrolled at > 100 sites worldwide. Clinical trial information: NCT02952534.

Abstract OT1-04-01: Estetrol for treatment of advanced ER+ breast cancer

Abstract Background information Estrogen therapy was the endocrine treatment of choice in postmenopausal women with advanced breast cancer for several decades since 1944. In the 1970s, estrogen therapy was replaced by tamoxifen. Tamoxifen showed similar regression rates but less toxicity as compared to estrogen therapy and was therefore considered preferred. Recently, estrogen therapy has gained new interest as several clinical studies showed clinical benefit in heavily pre-treated patients with advanced breast cancer after long-term estrogen deprivation. Estrogen therapy is an effective treatment for breast cancer but it has a negative safety reputation, especially related to the cardiovascular (CV) system. The fetal estrogen estetrol (E4) might be a new treatment option for patients with advanced breast cancer. It has less interference with liver function and is expected to be less harmful for the CV system compared to other estrogens whereas data from non-clinical and clinical studies suggest anti-tumor effects of E4 in breast tumors. Hypothesis The fetal estrogen E4 may have anti-tumor effects in patients with advanced ER+ breast cancer. It will most likely also reduce symptoms and signs of estrogen deficiency such as hot flushes, arthralgia, sleep disturbances, bone loss and cognition and improve patient's quality of life. Trial design and methods This is a multi-center, open-label, phase I/IIa, dose-escalation study with a 3 + 3 cohort design to determine the recommended dose of E4 for the treatment of patients with advanced breast cancer. Cohorts of at least 3 patients will receive doses of 20 mg, 40 mg and 60 mg E4 respectively, until the non-tolerable dose is determined or the maximum dose of 60 mg is reached. Patients will be treated once daily by oral administration for 12 weeks. In total 9-18 patients with advanced ER+ breast cancer will be enrolled at three centers in Germany. Objectives The main objectives of this study are to evaluate the safety, the effects on estrogen deficiency symptoms and the preliminary anti-tumor activity of E4 in patients with advanced breast cancer. Eligibility criteria Women who are more than 5 years postmenopausal, with ER+ and HER2-negative locally advanced and/or metastatic breast cancer are eligible for inclusion. In addition, patients should have failed on anti-estrogen treatment with tamoxifen and aromatase inhibitors. Patients with a history of venous or arterial thromboembolic disease or a known defect in the blood coagulation system will be excluded as well as patients who have used treatment with fulvestrant within 6 months prior to start of E4 treatment. Statistical methods Statistical tests used in this study are exploratory only. No confirmatory statistical test procedure is envisaged. Contact information For further information regarding the study, please contact Dr Carole Verhoeven (cv@pantarheibio.com). Citation Format: Verhoeven C, Schmidt M, Hönig A, Dünnebacke J, Dutman E, Krijgh J, Coelingh Bennink H. Estetrol for treatment of advanced ER+ breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT1-04-01.

Lym-1 Chimeric Antigen Receptor T Cells Exhibit Potent Anti-Tumor Effects against B-Cell Lymphoma.

T cells expressing chimeric antigen receptors (CARs) recognizing CD19 epitopes have produced remarkable anti-tumor effects in patients with B-cell malignancies. However, cancer cells lacking recognized epitopes can emerge, leading to relapse and death. Thus, CAR T cells targeting different epitopes on different antigens could improve immunotherapy. The Lym-1 antibody targets a conformational epitope of Human Leukocyte Antigen-antigen D Related (HLA-DR) on the surface of human B-cell lymphomas. Lym-1 CAR T cells were thus generated for evaluation of cytotoxic activity towards lymphoma cells in vitro and in vivo. Human T cells from healthy donors were transduced to express a Lym-1 CAR, and assessed for epitope-driven function in culture and towards Raji xenografts in NOD-scidIL2Rgammanull (NSG) mice. Lym-1 CAR T cells exhibited epitope-driven activation and lytic function against human B-cell lymphoma cell lines in culture and mediated complete regression of Raji/Luciferase-Green fluorescent protein (Raji/Luc-GFP) in NSG mice with similar or better reactivity than CD19 CAR T cells. Lym-1 CAR transduction of T cells is a promising immunotherapy for patients with Lym-1 epitope positive B-cell malignancies.

Successful treatment of ovarian cancer with apatinib combined with chemotherapy

Rationale:The standard treatment for ovarian cancer is chemotherapy with 2 drugs (taxanes and platinum drugs). However, the traditional combination of the 2 drugs has many adverse effects (AEs) and the cancer cells will quickly become resistant to the drugs. Apatinib is a small-molecule antiangiogenic agent which has shown promising therapeutic effects against diverse tumor types, but it still remains unknown whether apatinib has an antitumor effect in patients with ovarian cancer. Herein, we present a successfully treated case of ovarian cancer using chemotherapy and apatinib, in order to demonstrate the effectiveness of this new combined regimen in ovarian cancer.Patients concerns:A 51-year-old Chinese woman presented with ovarian cancer >4.5 years. The disease and the cancer antigen 125 (CA-125) had been controlled well by surgical treatment and following chemotherapy. However, the drugs could not control the disease anymore as the CA-125 level was significantly increasing.Diagnosis:Ovarian cancer.Interventions:The patient was treated with apatinib combined with epirubicin. Apatinib was administered orally, at an initial daily dose of 500 mg, and was then reduced to 250 mg qd after the appearance of intolerable hand–foot syndrome (HFS) and oral ulcer. Then, the oral ulcer disappeared and the HFS was controlled by dose adjustment, oral vitamin B6, and hand cream application.Outcomes:The CA-125 reverted to the normal value after treatment with the new regimen. Magnetic resonance imaging showed that the original tumor lesions had disappeared. Apatinib monotherapy as maintenance therapy was then used to successfully control the cancer with a complete response. Our study is the first, to our knowledge, to report the therapeutic effects of apatinib and epirubicin on ovarian cancer.Lessons:Apatinib combined with chemotherapy and apatinib monotherapy as maintenance therapy could be a new therapeutic strategy for ovarian cancer, especially adenocarcinomas.

Personalized neoantigen vaccines: A new approach to cancer immunotherapy

Neoantigens arise from somatic mutations that differ from wild-type antigens and are specific to each individual patient, which provide tumor specific targets for developing personalized cancer vaccines. Decades of work has increasingly shown the potential of targeting neoantigens to generate effective clinical responses. Current clinical trials using neoantigen targeting cancer vaccines, including in combination with checkpoint blockade monoclonal antibodies, have demonstrated potent T-cell responses against those neoantigens accompanied by antitumor effects in patients. Personalized neoantigen vaccines represent a potential new class of cancer immunotherapy.

Abstract 449: Reduced argininosuccinate synthetase expression in refractory sarcomas: impacts on therapeutic potential and drug resistance

Abstract Introduction: Treating drug-resistant sarcomas remain a major challenge. The present study aimed to identify a novel therapy for drug-resistant sarcomas based on a metabolic errors involving argininosuccinate synthetase1 (ASS1). Methods: We assessed the expression of ASS1 and P-glycoprotein (P-gp) in osteosarcoma (KHOS), doxorubicin (Dox)-resistant osteosarcoma (KHOSR2), epithelioid sarcomas (ES-X and VAESBJ), alveolar soft part sarcoma (ASPS-KY), and each clinical specimen. Each cell was cultured in arginine-containing and arginine-free media. Cell growth was assessed using an XTT assay and flow cytometry. We analyzed the induction of autophagy in arginine-free medium. Moreover, we assessed the expression of P-gp in after suppressing ASS1 in Dox-sensitive cells (MCF-7, KHOS) and in after transfecting the ASS1 into Dox-resistant cells (ES-X, VAESBJ, ASPS-KY and KHOSR2). Results: The expression of ASS1 was reduced in Dox-resistant sarcoma cells. Immunohistochemistry (IHC) and real-time PCR showed that there was interestingly an inverse relationship between the expression of ASS1 and the expression of P-gp. The inhibition of cellular proliferation with G1-arrest was shown to lead to autophagy with arginine deprivation. In addition, the combination of autophagy inhibitor plus arginine deprivation was more effective than arginine deprivation alone. In cells in which the expression of ASS1 was suppressed, the expression of P-gp was upregulated in comparison to negative controls. Discussion: These results indicate that the reduced expression of ASS1 expression in Dox-resistant sarcomas may contribute to drug resistance. ASS1 deficiency is a potential target for novel drug therapies. The combination of arginine deprivation therapy and an autophagy inhibitor may have anti-tumor effects in refractory sarcomas. Significance: As the induction of autophagy by the deprivation arginine may have a pro-survival role in patients with ASS1-deficient sarcomas, the combination of arginine deprivation therapy with autophagy modulators might potentiate anti-tumor effects in patients with drug-resistant sarcomas. Citation Format: Eisuke Kobayashi, Youngji Kim, Daisuke Kubota, Yoshiyuki Suehara, Akira Kawai, Shigehisa Kitano. Reduced argininosuccinate synthetase expression in refractory sarcomas: impacts on therapeutic potential and drug resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 449. doi:10.1158/1538-7445.AM2017-449

Association Between High-Avidity T-Cell Receptors, Induced by α-Fetoprotein−Derived Peptides, and Anti-Tumor Effects in Patients With Hepatocellular Carcinoma

Levels of α-fetoprotein (AFP) are measured for surveillance and diagnosis of hepatocellular carcinoma (HCC). We performed a phase 1 trial to evaluate the safety and efficacy of AFP-derived peptides as an anti-tumor vaccine for patients with advanced HCC, and characterized induction of AFP-specific T-cell receptors (TCRs). We performed a prospective study of 15 patients with HCC seen at Kanazawa University Hospital in Japan from March 2010 through March 2012. Each patient was given a subcutaneous injection of 3 mg AFP-derived peptides (AFP357 and AFP403) in an emulsion with incomplete Freund's adjuvant every other week for at least 6 weeks. Patients were evaluated every 8 weeks by radiologic imaging; adverse events and toxicities were categorized and graded using the common terminology criteria for adverse events. Criteria for discontinuation included unacceptable toxicities and disease progression defined as progressive disease using the Response Evaluation Criteria In Solid Tumors criteria. Patients' immune responses were monitored using an interferon-gamma enzyme-linked immunospot assay. Peptide-specific TCRs were assessed using a rapid TCR cloning and evaluation system. The observation period was 730 days. A complete response was defined as the disappearance of all tumors; stable disease was defined as tumors whose total diameter remained between >70% and <120% of the baseline measurement, without new lesions. We did not observe any serious adverse reactions to the peptides, which were well tolerated. Of the 15 patients who received at least 3 injections, 5 (33%) had an immune response to the peptides. One of the 15 patients had a complete response and disease stabilized in 8 patients. In 4 of the 15 patients, we detected AFP357-specific CD8 T cells; we cloned 14 different TCRs with different avidities for the peptide. A TCR with the highest avidity was observed in the patient who achieved a complete response for more than 2 years. In a phase 1 trial, administration of AFP-derived peptides to 15 patients with HCC did not cause adverse events and produced T cells with receptors that reacted to the peptides; 1 patient had a complete response and tumor growth slowed in 8 patients. T cells from the patient with a complete response expressed a highly functional TCR induced by the peptide vaccines. UMIN-CTR no: UMIN000003514.

Abstract B082: Migratory T cells demonstrate superior persistence and enhanced tumor control

Abstract Adoptive cell therapy (ACT) based on the transfer of chimeric antigen receptor (CAR) T cells rendered specific for CD19 has demonstrated significant anti-tumor effects in patients with refractory CD19+ B-cell malignancies. There are however no biomarkers that can predict the potency of T-cell infusion products and thus the ability to enrich functionally superior cells is lacking. Existing clinical data supports at least two important functions of the T cells in mediating tumor regression: (a) immediate cytotoxicity to enable tumor cell killing, and (b) long-term persistence to ensure lasting and durable responses. We demonstrate here that migratory capacity of T cells can be used as a biomarker to segregate functionally superior cells that display enhanced polyfunctionality in vitro and superior tumor control in vivo. The simplicity of sorting cells based on motility and the scalability of the approach imply that these can be routinely adapted in standard GMP settings to enrich for functional T cells among any heterogeneous population. Populations of CD19-specific chimeric antigen receptor (CAR) T cells were biomanufactured using our standard clinical protocol. Timelapse Imaging In Nanowell Grids (TIMING) was used to enable the simultaneous quantification of the interaction between thousands of individual tumor-specific CD8+ T cells and multiple tumor cells. These results demonstrated that IFN-gamma secretion was the most common function elicited upon tumor cell conjugation. We found that CD8+ T cells with killing ability, especially serial killing ability, required shorter durations of target cell conjugation in comparison to IFN-gamma secreting mono-functional cells, indicating rapid synapse termination by T cells capable of killing versus cytokine secretion. Tracking the velocities of these cells by time-lapse imaging revealed that these serial killer T cells (with or without IFN-gamma secretion) had a high out-of-contact basal motility. In order to gain a better understanding of the phenotypic characteristics of the migratory T cells, we performed molecular profiling of T cells identified only by their basal motility (in the absence of tumor cells) using single-cell multiplexed transcriptional profiling, microscopy and flow cytometry, and found that the costimulatory molecules CD2 and CD244, and the chemokine receptor CXCR3 were expressed at higher levels in highly motile T cells compared to the non-motile T cells. In order to test the hypothesis that migratory capacity can serve as a biomarker T cell polyfunctionality, we next sorted motile cells using a modified migration assay, and confirmed that the migrating cells were enriched in highly motile cells. We characterized these cells phenotypically by flow-cytometry and demonstrated that T-cell differentiation markers including CCR7, CD95 and CD45RA were not differentially expressed between the motile and non-motile cells. Consistently however, the migrated cells displayed superior killing and serial killing in comparison to the non-migrated T cells. This superior in vitro polyfunctionality of migratory T cells was confirmed in a mouse xenograft model of leukemia in which motile CAR+ T cells were superior in controlling the disease in comparison to either their non-motile counterparts or the parent unsorted population. In aggregate, these results demonstrate the utility of our TIMING single cell methodology in uncovering not only the dynamic profile of T-cell behavior but also the ability to identify subpopulations of T-cell with enhanced polyfunctionality. Our studies support the use of motility as a surrogate and selective marker of higher CAR+ T cell bioactivity. These results also open up avenues to molecularly engineer T cells for an increased motility that could translate to better in vivo outcomes. Note: This abstract was not presented at the conference. Citation Format: Gabrielle Romain, Harjeet Singh, Ivan Liadi, Jay R Adolacion, Laurence J.N. Cooper, Navin Varadarajan. Migratory T cells demonstrate superior persistence and enhanced tumor control [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B082.

Sustained Remissions Following Chimeric Antigen Receptor Modified T Cells Directed Against CD19 (CTL019) in Patients with Relapsed or Refractory CD19+ Lymphomas

BACKGROUND: Autologous T cells genetically modified to express a chimeric antigen receptor consisting of an external anti-CD19 single chain antibody domain with CD3ζ and 4-1BB signaling domains (CTL019 cells) can mediate potent anti-tumor effects in patients (pts) with relapsed or refractory chronic lymphocytic and acute lymphoblastic leukemias. We are conducting a phase IIa clinical trial to evaluate the safety and efficacy of CTL019 cells in pts with relapsed or refractory CD19+ non-Hodgkin lymphomas (NHL).METHODS: Pts with CD19+ diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), or mantle cell lymphoma (MCL) with no available curative treatment options, a limited prognosis (<2 years anticipated survival), and responsive or stable disease with most recent therapy are eligible. Pts with DLBCL have residual disease after primary and salvage therapies and are not eligible for autologous stem cell transplant (ASCT) or have relapsed or residual disease after ASCT; FL pts have progression of lymphoma <2 years after second or higher line of therapy (not including single agent monoclonal antibody therapy); MCL pts have relapsed, residual, or progressive disease after rituximab-chemotherapy combination therapy and are not appropriate for transplant or have relapsed after transplant. After steady state apheresis to collect peripheral blood leukocytes, pts receive lymphodepleting chemotherapy based on disease burden, histology, and past therapies. One to 4 days after chemotherapy, pts receive a single dose of CTL019 cells by intravenous infusion. Peripheral blood and marrow samples are collected for immunophenotypic, cytokine, and molecular studies at pre-specified times after T cell infusion. Initial tumor response assessment is performed 3 months after T cell infusion using International Working Group response criteria. Enrollment started in February 2014; data reported here are through July 26, 2015.RESULTS: To date, 38 pts have enrolled (DLBCL 21; FL 14; MCL 3). The median age is 56 years (range: 25-77), male: female ratio is 22:16, median number of prior therapies is 4 (range: 1-10), and number of pts with prior transplant is 12 (32%; 11 ASCT, 1 allotransplant). Ann Arbor stages at enrollment are: Stage IV 23 pts (61%), Stage III 7 pts (18%), Stage II 6 pts (16%), Stage 1E 2 pts (5%); 11 pts (29%) had bone marrow involvement. LDH was increased in 28 pts (74%). ECOG PS was 0 in 16 pts (42%) and 1 in 22 pts (58%). As of July 26, 2015, 24 patients have received the protocol-specified dose of CTL019 cells (13 DLBCL; 9 FL; 2 MCL). Lymphodepleting chemotherapy regimens were bendamustine (6 pts), cyclophosphamide (11 pts), cyclophosphamide-fludarabine (1 pt), modified EPOCH (3 pts), and radiation-cyclophosphamide (3 pts). Median total CTL019 cell dose is 5.00e8 (range: 1.79e8 - 5.00e8); median CTL019 cell dose/kg is 5.84e6 (range: 3.08e6-8.87e6). Median peak CTL019 cell expansion in blood occurred 7 days after infusion (range: 2-14 days); there was no difference in peak expansion between responders and non-responders. Cytokine release syndrome (CRS) occurred in 16 pts (14 grade 2; 1 grade 3; 1 grade 4) and did not predict response. Neurologic toxicity occurred in 3 pts: 2 episodes of delirium (1 grade 2, 1 grade 3) and one possibly related grade 5 encephalitis. 22 pts are evaluable for response (DLBCL 13, FL 7, MCL 2). Overall response rate (ORR) at 3 months is 68% (15/22): DLBCL 54% (7/13); FL 100% (7/7); MCL 50% (1/2). At the median follow-up 11.7 months, progression-free survival (PFS) from CTL019 infusion is 62% (DLBCL 43%; FL 100%). For responders at median follow up, response duration is 83% for DLBCL and 100% for FL.CONCLUSIONS: These results demonstrate that CTL019 cells can be prepared from extensively pretreated pts with active NHL and can induce durable responses with toxicity that is less than reported for chronic lymphocytic and acute lymphoblastic leukemias. [Display omitted] DisclosuresSchuster:Phamacyclics: Consultancy, Research Funding; Novartis: Research Funding; Gilead: Research Funding; Janssen: Research Funding; Nordic Nanovector: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding; Genentech: Consultancy; Hoffman-LaRoche: Research Funding. Svoboda:Seattle Genetics: Research Funding; Celgene: Research Funding; Celldex: Research Funding; Immunomedics: Research Funding. Dwivedy Nasta:BMS: Research Funding; Millenium Takeda: Research Funding. Porter:Genentech: Other: Spouse Employment; Novartis: Patents & Royalties, Research Funding. Mato:Celgene Corportation: Consultancy, Research Funding; Genentech: Consultancy; Pharmacylics: Consultancy, Research Funding; Pronai Pharmaceuticals: Research Funding; AbbVie: Consultancy, Research Funding; Janssen: Consultancy; TG Therapeutics: Research Funding; Gilead: Consultancy, Research Funding. Lacey:Novartis: Research Funding. Melenhorst:Novartis: Research Funding. Chew:Novartis: Patents & Royalties. Hasskarl:Novartis: Employment, Equity Ownership. Shah:Novartis: Employment, Equity Ownership. Wasik:Janseen and Novartis: Research Funding. Zheng:Novartis: Patents & Royalties. Levine:Novartis: Patents & Royalties, Research Funding. June:Novartis: Patents & Royalties, Research Funding.

Abstract ED01-02: Gene-modified T cells as biotherapeutics for cancer

Abstract Adoptive immunotherapy of T cells may have significant advantages over alternative immunotherapeutic approaches such as cancer vaccines since the phenotype, activity and specificity of expanded cells can be analyzed prior to injection. T cells can be genetically engineered prior to infusion to modify the antigens they target, increase their potency, and reduce their susceptibility to tumor-mediated immune inhibition. Genetic modification also allows T cells to be tracked in vivo to learn their fate. Adoptive transfer of T cells has been most successful after hematopoietic stem cell transplantation (HSCT) as prophylaxis and therapy for viral associated disease. In addition, the adoptive transfer of tumor infiltrating lymphocytes (TILs) in combination with lymphodepleting chemotherapy has shown promising long-term antitumor effects in patients with melanoma. Lastly, the adoptive transfer of T cells that have been genetically engineered to be tumor specific has resulted in impressive clinical responses, especially in patients with hematological malignancies. Despite these successes, clinical studies have also highlighted current limitations of adoptively transferred immune cells, including limited expansion in vivo, lack of homing to tumor sites, and toxicities due to recognition of normal tissues. In my talk I will review the current status of T-cell therapy for cancer with special focus on solid tumors and genetically modified T cells. Citation Format: Stephen Gottschalk. Gene-modified T cells as biotherapeutics for cancer. [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 ED01-02.

Abstract A47: Clinical profile of ASP8273, a mutant-selective EGFR inhibitor, in subjects with EGFR-mutation positive non-small cell lung cancer: interim results from an ongoing, phase 1, open-label, dose-escalation study

Abstract Introduction: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) have demonstrated antitumor effects in patients with EGFR-mutant lung cancers; however, within a year, patients typically become resistant to TKI treatment. ASP8273 is a third-generation, once daily, orally administered, irreversible EGFR TKI that selectively inhibits EGFR mutations (e.g., exon 19 deletions, L858R, exon 20 insertion) as well as a secondary mutation associated with TKI resistance (T790M). Methods: ASP8273 is under evaluation in an ongoing, Phase 1 dose-escalation study conducted in the United States. Subjects diagnosed with EGFR mutation-positive non-small cell lung cancer (NSCLC) previously treated with an EGFR TKI were enrolled into the dose escalation cohort (25-500 mg) and response expansion (100-400 mg) cohorts. Response expansion cohorts enrolled subjects with EGFR T790M mutation and required submission of tissue samples for central confirmatory testing. Primary endpoint was tolerability assessed via adverse events (AEs) monitoring; secondary endpoints were pharmacokinetic (PK) parameters and antitumor activity based on RECIST 1.1 criteria. Results: As of June 18, 2015, 69 subjects (19 M/50 F) with a median age of 64 years (range: 38-85 years) had been enrolled into the dose escalation (n = 34) and response expansion (n = 35) cohorts. All patients had EGFR mutation(s); exon 19 deletions, L858R, and exon 20 insertions were identified in 54%, 17%, and 3% of subjects, respectively. EGFR T790M mutation was confirmed in 51% of subjects. Diarrhea, nausea, and fatigue (all Grades) were the most common treatment-emergent and treatment-related AEs. Hyponatremia (n = 8), anemia (n = 2), diarrhea (n = 2), nausea (n = 2), and progressive disease (n = 2) were the only Grade ≥3 treatment-emergent AEs reported in ≥2 subjects; serious AEs reported in ≥2 subjects were hyponatremia (n = 2), nausea (n = 2), and progressive disease (n = 2). ASP8273 exposure appeared dose proportional with peak concentration occurring approximately 1-4 h after administration with a half-life of 6-14 h. Of the 45 subjects treated with ASP8273 100-500 mg with evaluable data, partial response (PR) has been achieved by 42% (19/45) subjects. PR was reached by 12 of the 25 (48%) T790M-positive subjects, 3 of the 6 (50%) T790M-negative subjects, 4 of the 14 (29%) of subjects with unknown T790M status, and 1 of the 2 (50%) subjects with a confirmed exon 20 insertion. Conclusions: ASP8273, at doses &amp;lt;400 mg/day, was generally well tolerated with dose-proportional PK. At doses of ≥100 mg, ASP8273 demonstrated antitumor activity in subjects with EGFR mutation-positive NSCLC, including subjects with and without EGFR T790M and patients with EGFR exon 20 insertions. Citation Format: Helena Yu, Geoffrey R. Oxnard, Alexander Spira, Leora Horn, Jared Weiss, Yan Feng, Howard West, Giuseppe Giaccone, Tracey Evans, Ronan Kelly, Tanya Fleege, Srinivasu Poondru, Fei Jie, Kouji Aoyama, Debbie Whitcomb, Anne Keating, Andrew Krivoshik. Clinical profile of ASP8273, a mutant-selective EGFR inhibitor, in subjects with EGFR-mutation positive non-small cell lung cancer: interim results from an ongoing, phase 1, open-label, dose-escalation study. [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 A47.

Role of Dose on Survival in Adjuvant Chemoradiation Pancreatic Cancer

Purpose/Objective(s): ACEi and ARB are commonly prescribed medications in the management of hypertension and diabetes. Pre-clinical and clinical data has suggested mitigating effects of these drugs on radiationinduced lung injury, which has implications for thoracic radiation therapy (RT). Whether ACEi/ARBs have a negative effect on tumor response still needs to be elucidated. In this study, we examined the correlation between ACEi/ARB and incidence of pCR as a surrogate for anti-tumor effect in patients receiving trimodality therapy for esophageal cancer. Materials/Methods: Between March 2000 and July 2012 135 patients with esophageal cancer were treated with NA-CRT followed by esophagectomy at our institution. The median age at diagnosis was 59 years (range, 26-82). The cohort was dominated by male patients (86%), distal esophageal primary (89%) and adenocarcinoma histology (76%). Predominant stage distribution was stage III (47%) and stage II (36%). Median radiation dose was 50.4 Gy (range 45.0-56.4Gy). Most common concurrent chemotherapy regimen was Cisplatin/5-Fu (59%). Primary endpoint was pCR rates with secondary endpoints of overall survival (OS) and progression free survival (PFS). Chi-square analysis along with univariate and multivariate Kaplan-Meier and Cox Regression analysis were performed. Results: With a median follow-up of 2.1 years, estimated median OS and PFS for the entire cohort were 2.7 years (95% CI: 2.0-3.4) and 2.8 years (95% CI: 1.9-3.7). 45 patients (33%) were taking ACEi/ARB at the time of radiation oncology consultation compared to 90 (67%) patients not taking ARBs. There were no significant differences in the distribution of key baseline variables between the two groups. The pCR rates with and without ACEi/ARB use were 36% and 43%, respectively (pZ0.39). Median OS and PFS in this group were 2.4 and 1.7 years, respectively. 3-year OS with and without ACEi/ARB use was 38.1% and 47.2% respectively, pZ0.2. Similarly, 3-year PFS was 42.9% and 47.6% respectively, pZ0.94. On multivariate analysis including use of ACEi/ARB in the model, none of the baseline characteristics impacted OS (borderline significance for N-stage, p < 0.1) and only advanced nodal status was associated with worse PFS (HRZ1.9, 95% CI 1.1-3.3, pZ0.03) with borderline significance of anatomical location and gender (p < 0.1). Conclusion: In our study, the use of ACEi/ARB was not associated with inferior pCR rates, OS or PFS. Validation in larger prospective databases with longer follow up is necessary to assess confounding effect of associated medical comorbidities on survival. If validated, then this absence of a negative impact supports their development as mitigators of radiation induced lung injury. Author Disclosure: J. Hyder: None. H. Boggs: None. M.D. Chuong: None. M. Suntharalingam: None. W. Burrows: None. N. Horiba: None. D.P. Zandberg: None. T.N. Tyer: None. E.P. Cohen: Research Grant; Department of Veterans Affairs. review of policy, planning meeting; Cancer and Kidney International Network. Z. Vujaskovic: None. P. Mohindra: None.

Abstract IA10: CARs for leukemia and beyond?

Abstract Relapsed hematologic malignancies pose a substantial unmet therapeutic challenge despite aggressive therapies. Engineered T cells have shown promise for a variety of malignancies and chronic infections. In this session we will review the current status of trials testing chimeric antigen receptor (CAR)-modified T cells for acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myelogenous leukemia (AML) and for myeloma. As of April 2014, twenty-five children and 5 adults with relapsed or refractory ALL were treated with anti-CD19:4-1BB:CD3zeta CAR T cells (CTL019). Complete remissions (CR) were achieved in 27/30 patients (90%). CTL019 cells proliferated up to 1000-fold and were detectable in blood, bone marrow, and cerebrospinal fluid of responding patients. Sustained remissions were achieved in 15/22 evaluable patients with median follow-up of 7 months (2-24 months), with event-free survival of 67% (95% confidence interval [CI], 51% to 88%) and overall survival of 78% (95% CI, 65% to 95%) measured at 6 months. CTL019-mediated B cell aplasia persisted for up to 2 years and is ongoing. Cytokine release syndrome (CRS) was observed in all patients. Severe CRS, seen in 27% of patients, was associated with high disease burden and was effectively treated with the IL-6 receptor antibody tocilizumab. More than 50 patients with advanced refractory chronic lymphocytic leukemia have been treated with CTL019. Two of the first three patients treated remain in complete remission nearly 4 years after infusion. An ongoing randomized phase II trial testing a high and a low dose of CTL019 has not shown a difference in the response rate. The lack of an obvious dose response rate is consistent with the high level proliferation of CAR T cells in vivo and suggests that once a threshold dose is reached, further dose escalation does not increase efficacy. Persistent B cell aplasia is observed in responding patients (more than 3 years in CLL patients and more than 2 years in pediatric ALL patients). No patient with persistent B cell aplasia has relapsed with CD19+ tumor. A major issue in the field is whether it is necessary to have ongoing immunosurveillance by CAR T cells or whether they induce “sterile remissions” where every last tumor cell is eradicated. CAR T cells can target very low levels of targets expressed at the cell surface. Because some myeloma cells express low levels of CD19, and because B cells may be a precursor of malignant myeloma cells, an ongoing pilot trial is testing whether CTL019 cells might recognize and eliminate malignant cells in patients with advanced plasma cell myeloma. In preclinical studies we have found that CD33 and CD123 CAR T cells have potent therapeutic effects in mice bearing xenografts with AML. At issue is whether off tumor toxicity on normal cells will be tolerable with CD33 and CD123 specific CARs. In summary, CAR-modified T cell therapy directed against CD19 is highly effective as salvage therapy for children and adults with relapsed/refractory ALL and CLL. Moreover, long-term remissions may be possible in some patients. Our findings support the advancement of CAR-modified T cell therapy into multicenter phase 2 clinical trials. 1. M. Kalos, C. H. June, Adoptive T cell transfer for cancer immunotherapy in the era of synthetic biology. Immunity 39, 49 (2013). 2. S. A. Grupp et al., Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. New England Journal of Medicine 368, 1509 (2013). 3. D. L. Porter, B. L. Levine, M. Kalos, A. Bagg, C. H. June, Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia New England Journal of Medicine 365, 725 (2011). 4. M. Kalos et al., T cells expressing chimeric receptors establish memory and potent antitumor effects in patients with advanced leukemia. Science Translational Medicine 3, 95ra73 (2011). 5. S. Maude et al., Sustained Remissions with Chimeric Antigen Receptor T Cells for Leukemia. New England Journal of Medicine, in press (2014). Citation Format: Carl H. June, David Porter, Stephan Grupp, Bruce L. Levine. CARs for leukemia and beyond? [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr IA10.

Abstract CT124: A phase II randomized double blind study of curcumin with preoperative capecitabine and radiation therapy followed by surgery for rectal cancer

Abstract Introduction: In vivo studies show that curcumin, a component of turmeric (Curcuma longa), inhibits signal transduction pathways involved in tumor growth and angiogenesis, induces apoptosis and potentiates the radioresponse of cancer cells by inducing NF-kB activity. However no study has validated its anti-tumor effect in patients undergoing cancer treatment. We performed a randomized double blinded study in patients with locally advanced rectal cancer to assess the efficacy of a combination of capecitabine and radiation therapy with or without curcumin, using pathological complete response (pCR) rate as a surrogate for overall clinical outcomes. Patients and Methods: Between September, 2008 and September, 2010, patients with biopsy-proven, locally advanced adenocarcinoma of the rectum were enrolled and randomized to placebo and curcumin treatment arms in a 1:2 ratio. All patients received pre-operative radiation therapy (50.4 Gy/28 fractions for 5-6 weeks) along with concurrent capecitabine (825 mg/m2 orally twice daily, only on days of radiation) followed by surgery after 6 weeks. Curcumin or placebo capsules (4 g orally, twice daily) were given throughout the chemoradiation therapy period and until surgery, typically 6 weeks later. Patients were evaluated at baseline, weekly during chemoradiation and just before surgery using the MD Anderson symptom inventory (MDASI) and Brief Fatigue Inventory (BFI) questionnaires. In addition, weekly clinical assessment and monitoring of hematological and biochemical parameters was done throughout the treatment course to evaluate treatment-related toxicity. The pharmacokinetics of curcumin was studied using blood samples taken before and one hour after curcumin intake during the second week of chemoradiation. The primary target outcome was pCR evaluated at the time of surgery. This study is registered with Clinicaltrials.gov, number NCT00745134. Results: 22 patients were enrolled in the study and 15 received curcumin. The median age was 61 years and majority were males (13, 59%). The median serum curcumin concentrations before and one hour after curcumin intake did not differ significantly (p = 0.33) and were 3.04 ng/mL (range, 1.24 to 18.88) and 3.32 ng/mL (range, 0.84 to 5.36) respectively. pCR was seen in two patients in the placebo arm and one patient in the curcumin arm (p = 0.23). Acute toxicity was relatively uncommon in both groups: grade 2 diarrhea (1, 7%), grade 2 dermatitis (5, 33%) and grade 3 diarrhea (1, 7%) in the curcumin arm; grade 2 dermatitis (1, 14%) and grade 3 diarrhea (1, 14%) in the placebo arm. Conclusion: Addition of curcumin to capecitabine and radiation therapy did not increase the rate of pCR in patients with rectal cancer. The low bioavailability of curcumin preparation used could explain the lack of efficacy noted in this study. Citation Format: Awalpreet S. Chadha, Sushovan Guha, Sunil Krishnan. A phase II randomized double blind study of curcumin with preoperative capecitabine and radiation therapy followed by surgery for rectal cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT124. doi:10.1158/1538-7445.AM2015-CT124

Adoptive immunotherapy: a new era for the treatment of cancer.

The early promise of adoptive immuno­ therapy is now coming to fruition with excit­ ing clinical responses being reported against various cancers. This has particularly been the case with adoptive transfer of tumor­infiltrat­ ing lymphocytes in patients with advanced malignant melanoma [1–3], transfer of chime­ ric antigen receptor (CAR) T cells targeting CD19 in patients with B­cell malignancies such as chronic lymphoid leukemia and acute lymphoblastic leukemia [4–7] and transfer of Epstein–Barr virus (EBV)­specific T cells against viral­induced malignancies such as post­transplant lymphoproliferative disorder (PTLD) [8,9]. However, for application of adoptive cellular therapy to a wider range of solid and hematological cancers, several chal­ lenges remain. In this special focus issue, we have invited several experts in the adoptive immunotherapy field to discuss these issues and propose potential strategies for enhancing the current success of this approach. Smith and Khanna discuss the use of adop­ tive T­cell therapy for EBV­induced cancers. This therapy has been very successful for PTLD, however, this is currently not the case for other EBV­induced cancers includ­ ing lymphoma and nasopharyngeal cancer. This review discusses various new strategies for altering the tumor microenvironment and increasing tumor immunogenicity. This includes adjunct­based approaches involving chemotherapy in combination with adop­ tive T­cell therapy which has shown some promising signs against nasopharyngeal can­ cer. Alternatively, targeted approaches for preferentially expanding T cells recognizing EBV­associated antigens LMP­1, LMP­2 or EBNA1 have showed some promising results in lymphoma patients. Beavis et al. discuss the negative effect of immune suppression pathways on the effi­ cacy of adoptive T­cell therapy. The recent success of immune checkpoint inhibitors blocking PD­1 and CTLA­4 pathways in patients with advanced cancer such as melanoma, renal cancer and non­small­ cell lung carcinoma suggests that immuno­ suppression can be effectively overcome resulting in increased antitumor immunity in some patients. This has raised the pos­ sibility that combining these drugs with other immunotherapies including adoptive T­cell immunotherapy may lead to further enhancing antitumor effects in patients par­ ticularly for less immunogenic cancers. This review discusses several nongenetic and genetic strategies that may be employed to overcome tumor­induced immune suppres­ sion for enhancing the efficacy of adoptive Adoptive immunotherapy: a new era for the treatment of cancer

Why Chemotherapy Should be Given Early for Men with Metastatic Prostate Cancer.

Metastatic hormone-sensitive prostate cancer (mHSPC) is an incurable disease, and despite a high response rate to androgen-deprivation therapy (ADT), outcomes have not significantly changed for many decades. Earlier attempts at multitargeted strategies with the addition of cytotoxic chemotherapy to ADT did not affect survival. As more effective therapies are emerging, including cytotoxic therapy for patients with metastatic castrate-resistant prostate cancer (mCRPC), there is increasing interest for testing these drugs earlier in the disease course. The premise is that agents with clinical benefit in advanced mCRPC may have a better effect if used preemptively before the development of significant resistance and to attack earlier de novo androgen resistant/independent clones. The recent results of the phase III clinical trial E3805 investigating ADT with or without docetaxel in mHSPC provide compelling support for this strategy. Docetaxel combined with ADT significantly improved overall survival from 44 to 57.6 months (p=0.0003), particularly in patients with high-volume disease (from 32.2 to 49.2 months; p=0.0006). Longer follow-up is needed to assess the effect on patients with low disease burden. Further studies are needed to further maximize the antitumor effect in patients with mHSPC and to investigate the effects of advancing therapy to this disease setting on the efficacy of respective agents in the castration-resistant setting.

Histone acetyltransferase PCAF accelerates apoptosis by repressing a GLI1/BCL2/BAX axis in hepatocellular carcinoma.

P300/CBP-associated factor (PCAF), a histone acetyltransferase (HAT), has been found to regulate numerous cell signaling pathways controlling cell fate by acetylating both histone and non-histone proteins. We previously reported that PCAF upregulates cell apoptosis by inactivating Serine/Threonine Protein Kinase 1 (AKT1) signaling and consequently inhibits hepatocellular carcinoma (HCC) cell growth. Here, we show that PCAF can directly acetylate cytoplasmic GLI1 protein at lysine 518, preventing its nuclear translocation and promoter occupancy, and consequently suppressing Hedgehog (Hh) signaling in HCC. Further, our results show that GLI1 can increase Bcl-2 expression and downregulate BAX. Interestingly, forced expression of PCAF reduced Bcl-2 expression, upregulated BAX and repressed cell apoptosis. Further, we provide evidence that knockdown of GLI1 abrogates the inhibitory effect of PCAF on the growth of HCC in vitro. PCAF was also found to sensitize HCC cells to 5-fluorouracil (5-FU) treatment by regulating GLI1/Bcl-2/BAX axis-dependent apoptosis. In vivo experiments also confirmed the regulatory effect of PCAF on the GLI1/Bcl-2/BAX axis and its synergistic antitumor effects with 5-FU. Gene expression microarray studies showed that PCAF was downregulated in HCC tissues compared with adjacent liver tissues and that PCAF expression was significantly associated with longer overall survival and recurrence-free survival after surgery. Together, these results show that PCAF can induce cell apoptosis by modulating a GLI1/Bcl-2/BAX axis that in turn suppresses HCC progression, and suggest that 5-FU may exert a stronger anti-tumor effect in patients with PCAF expression in HCC tumors.

Phase IIa Trial of Chimeric Antigen Receptor Modified T Cells Directed Against CD19 (CTL019) in Patients with Relapsed or Refractory CD19+ Lymphomas

BACKGROUND: Autologous T cells genetically modified to express a chimeric antigen receptor consisting of an external anti-CD19 single chain antibody domain with CD3ζ and 4-1BB signaling domains (CTL019 cells) can mediate potent anti-tumor effects in patients (pts) with relapsed or refractory chronic lymphocytic and acute lymphoblastic leukemias. We are conducting a phase IIa clinical trial to evaluate the safety and efficacy of CTL019 cells in pts with relapsed or refractory CD19+ non-Hodgkin lymphomas (NHL).METHODS: 30 evaluable pts are planned for analysis, including at least 8 with follicular lymphoma (FL), 8 with diffuse large B cell lymphoma (DLBCL), and 8 with mantle cell lymphoma. Eligible pts have CD19+ NHL with no available curative treatment options, a limited prognosis of several months to <2 years anticipated survival, and responsive or stable disease with most recent therapy. Pts with FL have progression of lymphoma within 2 years after second or higher line of therapy (not including single agent monoclonal antibody therapy); DLBCL pts have residual disease after primary therapy and are not eligible for autologous stem cell transplant (ASCT) or have relapsed or residual disease after ASCT. After steady state apheresis to collect peripheral blood leukocytes, pts receive lymphodepleting chemotherapy based on disease burden, histology, and past therapies. One to 4 days after chemotherapy, pts receive a single dose of CTL019 cells by intravenous infusion; total CTL019 target dose is 5 x 108 cells. Peripheral blood and marrow samples are collected for immunophenotypic, cytokine, and molecular studies at pre-specified times after T cell infusion. Initial tumor response assessment is performed 3 months after T cell infusion using International Working Group response criteria. Enrollment started in February 2014; data reported here are through July 30, 2014.RESULTS: To date, 23 pts (DLBCL 16; FL 7) have enrolled. The median age is 56 years (range: 25-77), male: female ratio is 14:9, median number of prior therapies is 4 (range: 1-8), and number of pts with prior ASCT is 9 (39%). Ann Arbor stages at enrollment are: stage IV 11 pts (48%); stage III 5 pts (22%); stage II 5 pts (22%); stage IE 2 pts (8%); 5 pts (22%) had bone marrow involvement. LDH was increased in 17 pts (74%). Three pts (DLBCL 2 pts; FL 1 pt) were removed from the trial before therapy due to progressive disease. As of July 30, 2014, 14 pts have received CTL019 T cell infusions. Pre-infusion chemotherapy regimens were EPOCH (1 pt); cyclophosphamide (7 pt); bendamustine (5 pts); cyclophosphamide-fludarabine (1 pt). Median CTL019 T cell dose is 5.8 x 106 cells / kg (range: 3.7 – 8.9 x 106). In vivo expansion of CTL019 cells was brisk; the median peak CTL019% of CD3+ cells in peripheral blood was 6.1% (range: 0.7-43.1%) for all patients, 17.3% (range: 3.9-43.1) for responders, and 4.95% (range: 0.7-7.3) for non-responders. Peak CTL019 cell expansion generally occurred around 7 days after T cell infusion. All patients developed fever following T cell infusion, attributed to cytokine release syndrome (CRS). Severity of CRS according to our novel grading scale (reported separately) was: 12 pts grade 2; 1 pt grade 3; 1 pt grade 4. One pt received steroids and tocilizumab for grade 4 CRS. CRS occurred within the first week of T cell infusion in all pts. Neurologic toxicity was observed in 2 pts (1 pt with grade 3 encephalopathy that resolved with corticosteroids; 1 pt with grade 3 dysarthria and grade 3 ataxia). There was no treatment-related mortality. Eight pts are evaluable for response (DLBCL 6; FL 2). Overall response rate at 3 months is 50% with 3 complete responses (DLBCL 2 pts; FL 1 pt) and 1 partial response (FL); 4 pts with DLBCL had progressive disease before or at initial response assessment.CONCLUSIONS: In this ongoing trial of CTL019 cells in relapsed or refractory NHL, 4 of the first 8 evaluable pts responded to therapy. These early results demonstrate that CTL019 cells can be prepared from previously treated pts with active NHL, can undergo robust in-vivo expansion, and can induce complete responses in pts with advanced, relapsed or refractory DLBCL and FL. Longer follow up will define toxicities, durability of response, and clinical benefit, as well as guide further development of this promising new therapeutic approach. DisclosuresSchuster:Novartis: Research Funding. Porter:Novartis: Patents & Royalties, Research Funding; Genentech (spouse employment): Employment. Mahnke:Novartis: Research Funding. Lacey:Novartis: Research Funding. Chew:Novartis: Patents & Royalties, Research Funding. Shah:Novartis: Employment. Hasskarl:Novartis: Employment. Litchman:Novartis: Employment. Frey:Novartis: Research Funding. Zheng:Novartis: Patents & Royalties, Research Funding. Levine:Novartis: Patents & Royalties, Research Funding. June:Novartis: Patents & Royalties, Research Funding.

Randomized, Phase II Dose Optimization Study of Chimeric Antigen Receptor Modified T Cells Directed Against CD19 (CTL019) in Patients with Relapsed, Refractory CLL

Randomized, Phase II Dose Optimization Study of Chimeric Antigen Receptor Modified T Cells Directed Against CD19 (CTL019) in Patients with Relapsed, Refractory CLL

Cytokine Release Syndrome (CRS) after Chimeric Antigen Receptor (CAR) T Cell Therapy for Relapsed/Refractory (R/R) CLL

CTL019 are autologous T cells genetically modified to express a chimeric antigen receptor (CAR) consisting of an external anti-CD19 domain with the CD3z and 4-1BB signaling domains, and mediate potent anti-tumor effects in patients (pts) with advanced, R/R CLL, ALL and NHL. CRS is the most serious toxicity of CTL019 therapy; symptoms can include fevers, nausea, myalgias, capillary leak, hypoxia, and hypotension.Standard CRS grading criteria are not applicable to CAR T cell therapies. To better capture clinical manifestations of CRS and guide intervention after CTL019, we devised a novel CRS grading scale. that was applied to 40 pts treated with CTL019 for R/R CLL; 14 pts on an initial pilot and 26 pts on an ongoing dose-optimization trial (reported separately).Our new CRS grading system is shown below. Pts were 80% male, a median age of 65 (range 51-78) and received a median of 4 prior therapies (range 1-10). 41% had known mutation at p53. 83% of 24 pts tested had unmutated IgVH. Response rate to CTL019 (CR+PR) was 42%. CRS was the major toxicity and occurred in 57% (23/40) of pts. CRS was gr 1 in 10%, gr 2 in 17%, gr 3 in 15% and gr 4 in 15%. Development of CRS correlated with response; 13/23 (57%) pts with CRS responded versus 4/17 (24%) pts without CRS responded (p=0.05). CRS was associated with elevations in IL-6, IFN-g, and other cytokines; details for 33 pts will be presented. Peak fold-increase over baseline for IL-6 was a median of 10.6x (range 0.28–649) and for IFN- g a median of 32.9x (1–7243x). For pts with CRS, this increase in IL-6 was a median of 23.5x compared to 1.86x in pts without CRS (p=0.001); and in IFN- g was a median of 97.2xin pts with CRS compared to 24.2x without (p=0.018). Increasing CRS severity was associated with peak fold change in IL-6 (p< 0.0001) and IFN- g (p=0.015). Notably, unlike cytokine changes associated with sepsis, TNF-a did not markedly increase during CRS.CRS occurred with a consistent and often dramatic increase in ferritin, C reactive protein (CRP), and hemophagocytosis, suggesting concurrent macrophage activation syndrome (MAS). Increasing CRS severity was associated with an increasing trend for peak ferritin (log scale, p<0.001) and peak CRP (p<0.001). The median peak ferritin was 13,463 ng/ml in pts with CRS compared to 378 in pts without (p<0.001). Median peak CRP was 16 mg/dl in pts with CRS compared to 3.86 in pts without (p=0.002). CRS required intervention in 8 pts. 1 pt was successfully treated with corticosteroids. Given marked increases in IL-6, 7 patients received the IL6-receptor antagonist tocilizumab with or without corticosteroids with resolution of CRS. Tocilizumab was given to 1/7 pts with gr 2 CRS, 1/6 pts with gr 3 and 5/6 pts with gr 4. Several pts also received corticosteroids and/or etanercept. All pts had resolution of CRS signs with no TRM from CRS.CRS is the most significant complication of CTL019 and can be life threatening. A novel CRS grading system was needed to identify CRS severity more accurately guide intervention timing. CTL019-related CRS is associated with a unique cytokine profile and has been manageable with anti-cytokine therapy in pts with R/R CLL. CRS appears to correlate with response of CLL to CTL019. Further study is needed to develop reliable methods to predict severity and minimize CRS toxicity without inhibiting anti-leukemia activity of CTL019.New CRS Grading System for CTL019Abstract 1983. TableGrade 1Grade 2Grade 3Grade 4Mild: Treated with supportive care such as anti-pyretics, anti-emeticsModerate: Requiring IV therapies or parenteral nutrition; some signs of organ dysfunction (i.e. gr 2 Cr or gr 3 LFTs) related to CRS and not attributable to any other condition. Hospitalization for management of CRS related symptoms including fevers with associated neutropenia.More severe: Hospitalization required for management of symptoms related to organ dysfunction including gr 4 LFTs or gr 3 Cr related to CRS and not attributable to any other conditions; this excludes management of fever or myalgias. Includes hypotension treated with IV fluids or low-dose pressors, coagulopathy requiring FFP or cryoprecipitate, and hypoxia requiring supplemental O2 (nasal cannula oxygen, high flow 02, CPAP or BiPAP). Pts admitted for management of suspected infection due to fevers and/or neutropenia may have gr 2 CRS.Life-threatening complications such as hypotension requiring “high dose pressors”, hypoxia requiring mechanical ventilation. DisclosuresPorter:Novartis: Patents & Royalties, Research Funding; Genentech (spouse employment): Employment. Off Label Use: Use of genetically modified T cells (CTL019) to treat CLL and use of tocilizumab to treat cytokine release syndrome.. Lacey:Novartis: Research Funding. Hwang:NVS: Research Funding. Frey:Novartis: Research Funding. Chew:Novartis: Patents & Royalties, Research Funding. Chen:Novartis: Research Funding. Kalos:Novartis: Patents & Royalties, Research Funding. Gonzalez:Novartis: Research Funding. Melenhorst:Novartis: Research Funding. Litchman:Novartis: Employment. Shen:Novartis: Employment. Quintas-Cardamas:Novartis: Employment. Wood:Novartis Pharma: Employment. Levine:Novartis: Patents & Royalties, Research Funding. June:Novartis: Patents & Royalties, Research Funding. Grupp:Novartis: Research Funding.