Unum Therapeutics Research Articles

Engineering CD70-Directed CAR-NK Cells for the Treatment of Hematological and Solid Malignancies

Advances in cellular immunotherapy have led to multiple FDA approvals for autologous CAR-T cell therapies in acute lymphoblastic leukemia (ALL), non-Hodgkin's lymphomas (NHL), and multiple myeloma (MM). While effective, autologous CAR-T therapies are limited by safety concerns, lack of scalability for patient derived starting material, and long vein-to-vein timelines. Allogeneic CAR-NK cell therapies have the potential to overcome these limitations by providing an off-the-shelf product capable of delivering clinical benefit without the safety and manufacturing challenges associated with CAR-T therapy. CAR-NK cell therapies are particularly attractive in AML as the inherent graft-versus-leukemia activity of NK cells can be effectively augmented by a CAR directed to an AML expressed antigen. CD70 expression is associated with several indications, including AML, NHL, and renal cell carcinoma (RCC), and it is an attractive target for CAR therapy in AML since it is highly expressed on leukemic stem cells and blasts and is absent in normal bone marrow hematopoietic stem cells. 1 While aberrant expression of CD70 is associated with several solid and hematological indications, its expression in normal tissue is restricted to immune cells including T, B, DC, and NK cells. 2 Here we demonstrate that CD70 is not expressed in resting peripheral blood NK cells but is strongly upregulated in response to NK cell activation by engineered feeder cells. Introduction of CARs targeting CD70 into activated NK cells leads to substantial reduction of NK cell expansion due to fratricide. While CD70 is expressed in activated NK cells, knockout (KO) of CD70 by CRISPR/Cas9 editing does not inhibit NK cell expansion nor impair endogenous cytotoxicity against K562 target cells. Using the non-viral TcBuster™ Transposon System (Bio-Techne), we were able to deliver transposons containing a CD70 CAR and an IL15 expression cassette while simultaneously knocking out CD70 by CRISPR/Cas9 in primary human peripheral blood NK cells. This single-step process resulted in >70% CAR integration/expression and >80% knockout of CD70. The resulting CD70 knockout CAR-NK cells were resistant to fratricide and expanded comparably to mock-engineered NK cells following feeder cell activation. The IL15 expression cassette enabled enhanced persistence of CAR-NK cells in vitro without exogenous cytokine support. In functional assays, CD70 KO NK cells engineered with the CD70 CAR and IL15 expression cassette mediated cytotoxicity against multiple CD70-positive tumor cell lines, expressed the degranulation marker CD107a (LAMP1), and expressed the cytokines IFNγ and TNFα. Overall, the results demonstrate the potential for targeting CD70 with CAR-NK cell therapy for the treatment of AML, RCC, and other CD70-positive malignancies while overcoming the risk posed by fratricide by engineering with a non-viral transposon delivery system in combination with CRISPR/Cas9 editing.1 Perna et al. 2017, Cancer Cell. 32:506-519.2 McEarchern et al. 2008, Clin Cancer Res. 14(23):7763-7772. DisclosuresChoi: Unum Therapeutics: Divested equity in a private or publicly-traded company in the past 24 months, Ended employment in the past 24 months. Walsh: Obsidian Therapeutics: Ended employment in the past 24 months. Khamhoung: Rubius Therapeutics, Inc.: Ended employment in the past 24 months. Johnson: Celsius Therapeutics: Current holder of stock options in a privately-held company, Ended employment in the past 24 months. Franco: KSQ Therapeutics: Current holder of individual stocks in a privately-held company, Ended employment in the past 24 months. Swiech: Agenus: Current holder of individual stocks in a privately-held company, Ended employment in the past 24 months; Unum Therapeutics: Divested equity in a private or publicly-traded company in the past 24 months, Ended employment in the past 24 months. Richardson: Novartis Pharma: Current equity holder in publicly-traded company; Obsidian Therapeutics: Current holder of stock options in a privately-held company, Ended employment in the past 24 months.

Adverse Events in Patients with Cancer Treated with Direct Oral Anticoagulants and Cancer Therapy

IntroductionFour direct oral anticoagulants (DOAC) have been approved for the treatment of venous thromboembolism VTE and prevention of stroke in patients with non-valvular atrial fibrillation (NVAF) in the USA: rivaroxaban, apixaban, edoxaban and dabigatran. Data regarding efficacy and safety of DOAC in the cancer population however are currently limited to very small cohorts in the large randomized trials for treatment of VTE in which many cancer patients did not meet eligibility requirements, or to retrospective studies and quality improvement initiatives. Despite major consensus guidelines recommending low molecular weight heparin (LMWH) as the preferred treatment for cancer-associated VTE, DOAC are commonly prescribed for cancer patients in both community and academic settings. Data on the safety and efficacy of DOAC in patients getting active cancer treatment are lacking. We aimed to characterize the use of DOAC in patients managed at an academic comprehensive cancer center, to examine the incidence of thrombotic and bleeding events among patients receiving active cancer therapy during the study period.MethodsFollowing IRB approval, a retrospective chart review was performed in patients treated at an academic comprehensive cancer center. Patients >18 years old who had a prescription written for a DOAC between June 2015 and December 2016 were identified. Patients were included if they were receiving DOAC for NVAF, acute VTE, and secondary prevention and had active cancer. Patients were assessed for baseline demographics, indications for anticoagulation, DOAC management strategies, arterial and venous thrombotic events and bleeding complications during treatment with DOAC. Descriptive statistics were used to analyze study outcomes.ResultsOf the 721 patients screened, 392 were patients with cancer of which 241 s were actively being treated with chemotherapy while on DOAC. The other 151 patients were not actively receiving treatment. VTE was the most common indication for DOAC use in 75% of cancer patients (n=297), followed by NVAF in20% (n=78). There were 15 patients with history of both NVAF and VTE, and 2 patients with TIA. Apixaban was used in 48% of patients; rivaroxaban in 47%; dabigatran in 4%, and edoxaban < 1%.Of the 392 evaluated cancer patients, 15 (3.83%) experienced thrombotic events with 11/15 new or recurrent VTE, 3/15 stroke, and 1/15 myocardial infarction while on DOAC. The VTE rate was strikingly higher in those patients receiving active cancer treatment at 4.15% compared to 0.66% in those not getting treatment. The rate of major bleeding and clinically overt bleeding was not different between the 2 groups and was approximately 4.5%. (table 1)ConclusionWe found in our retrospective analysis of DOAC use in cancer patients, that patients getting active cancer treatment had higher rates of primarily venous and arterial thrombotic events while treated with DOAC compared to those patients not getting active cancer treatment. The rate of VTE at 4.14% compares favorably with published rates for VTE recurrence for LMWH and VKA in randomized controlled trials and is roughly 7 times higher than the rate in our patients with cancer treated with DOAC but not getting active cancer treatment. Despite differences in rates of thrombotic events, the bleeding rates were the same, and also comparable to published rates, confirming the known increased risk of bleeding in cancer patients. While our results are promising, dedicated randomized controlled trials comparing DOAC to LMWH are required to truly determine the efficacy and safety of DOAC in cancer patients simultaneously receiving cancer treatment. [Display omitted] DisclosuresConnors:BMS: Consultancy, Other: Scientific Advisory Board; Pfizer/BMS -Alliance: Other: Independent review committe; Unum Therapeutics: Other: Data Safety Monitoring Board; boehringer Ingelheim: Other: Scientific Advisory Board.

Primary Analysis of Juliet: A Global, Pivotal, Phase 2 Trial of CTL019 in Adult Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Primary Analysis of Juliet: A Global, Pivotal, Phase 2 Trial of CTL019 in Adult Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Results from a Phase 1/2 Study of INCB050465, a Highly Selective and Highly Potent PI3Kδ Inhibitor, in Patients with Relapsed or Refractory B-Cell Malignancies (CITADEL-101)

Results from a Phase 1/2 Study of INCB050465, a Highly Selective and Highly Potent PI3Kδ Inhibitor, in Patients with Relapsed or Refractory B-Cell Malignancies (CITADEL-101)

Brentuximab Vedotin Plus Doxorubicin, Vinblastine, Dacarbazine (A+AVD) As Frontline Therapy Demonstrates Superior Modified Progression-Free Survival Versus ABVD in Patients with Previously Untreated Stage III or IV Hodgkin Lymphoma (HL): The Phase 3 Echelon-1 Study

Brentuximab Vedotin Plus Doxorubicin, Vinblastine, Dacarbazine (A+AVD) As Frontline Therapy Demonstrates Superior Modified Progression-Free Survival Versus ABVD in Patients with Previously Untreated Stage III or IV Hodgkin Lymphoma (HL): The Phase 3 Echelon-1 Study

Safety and Efficacy of Polatuzumab Vedotin + Obinutuzumab for Relapsed/Refractory NHL: A Phase 1b/2 Study

Background: Single-agent polatuzumab vedotin (pola) and obinutuzumab (G) demonstrated safety/clinical activity in separate B-cell non-Hodgkin lymphoma (B-NHL) trials. Methods: Open-label, non-randomised, phase 1b/2 study (ROMULUS) of patients with relapsed/refractory (R/R) B-NHL evaluating safety/efficacy of pola 1·8 mg/kg + G 1000 mg in 21-day cycles, up to eight cycles. Primary objectives were safety/tolerability and anti-tumour response. Findings: Eighty-eight patients were enrolled and received ≥1 dose of any study drug; 43 patients with R/R follicular lymphoma (FL) and 45 with R/R diffuse large B-cell lymphoma (DLBCL). Grade 3–4 AEs occurred in 48·5% (n=48/88) of patients, most commonly, neutropenia (18·6%; n=18). In R/R FL, the most frequent any-grade adverse event (AE) was fatigue (n=23/43; 53·5%) and in R/R DLBCL diarrhoea (n=16/45; 35·6%). In R/R FL, the complete response (CR) rate (by independent review committee) was 36·1% (n=13/36; 90% confidence interval [CI]: 22·9–51·2) with an objective response rate (ORR) of 66·7% (n=24/36; 90% CI: 51·7–79·5). The ORR in R/R DLBCL was 19·4% (n=6/31; 90% CI: 8·8–34·7; no CRs). In R/R FL, investigator-assessed median duration of response was 8·5 months (interquartile range [IQR]: 6×3–9×7) and in R/R DLBCL was 3·7 months (IQR: 3×3–not estimable [NE]); median progression-free survival was 11·5 months (IQR: 7×8-12×4) and 2·8 months (IQR: 1×5-6×3); and median overall survival was not reached and 10·7 months, respectively. Interpretation: While the anti-tumour activity of pola (1.8 mg/kg)-G in R/R DLBCL was modest, pola-G warrants further investigation as a treatment for R/R FL. Trial Registration: www.clinicaltrials.gov (NCT01691898). Funding Statement: F. Hoffmann-La Roche. Declaration of Interests: T.P. has received research support from AbbVie and Pharmacyclics, and reports advisory board participation for Genentech, Inc., Bayer, Gilead, Pharmacyclics, Incyte, and Seattle Genetics. M.B. has no disclosures; the clinical and intellectual work on this paper was performed prior to employment with the Cigna Corporation and does not reflect the opinions or support of the Cigna Corporation. A.I.C. has acted as a consultant and has received research funding from Genentech, Inc. J.E. has nothing to disclose. A.C. reports advisory board participation for Celgene, Janssen, and iQone, and has received lecture fees from Celgene, Janssen, F. Hoffman-La Roche Ltd, and Servier. C.D. has served as a consultant/advisory board participant for Bristol-Myers Squibb, Celgene, Merck, Genentech, Inc./F. Hoffman-La Roche Ltd, and Seattle Genetics, and has received research support from Seattle Genetics, Bristol-Myers Squibb, Merck, Genentech, Inc., Incyte, LAM Therapeutics, Millennium/Takeda, MEI Pharma, and Trillium. J.C. is an employee of F. Hoffmann-La Roche Ltd. D.R. was a consultant to Genentech, Inc. at the time the study was carried out. J.H. is an employee of Genentech, Inc. F.M. has participated in advisory boards for Celgene, F. Hoffman-La Roche Ltd, Gilead, Bristol-Myers Squibb, Epizyme, and Bayer, and reports receiving lecture fees from Celgene, Janssen, F. Hoffman-La Roche Ltd, and Novartis, and research support from AbbVie, Pharmacyclics, and advisory board fees from Genentech, Inc., Bayer, Gilead, Pharmacyclics, Incyte, and Seattle Genetics. I.W.F. has acted as a consultant for AbbVie, Seattle Genetics, TG Therapeutics, and Verastem Oncology, and has received research funding from Acerta Pharma, Agios, Calithera Biosciences, Celgene, Constellation Pharmaceuticals, Genentech, Inc., Gilead Sciences, Incyte, Infinity Pharmaceuticals, Janssen, Karo Pharma, Kite Pharma, Novartis, Pharmacyclics, Portola Pharmaceuticals, F. Hoffman-La Roche Ltd, TG Therapeutics, Trillium Therapeutics, AbbVie, ArQule, BeiGene, Curis Inc., FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem Oncology, Gilead Sciences, Astra Zeneca, Juno Therapeutics, Unum Therapeutics, and MorphoSys AG. Ethics Approval Statement: Institutional review boards/ethics committees approved the protocol. The study was conducted in accordance with the principles of the Declaration of Helsinki, the International Council for Harmonisation guidelines for Good Clinical Practice, and country-specific laws and regulations. All patients provided written informed consent.

Preliminary Clinical Results from a Phase 1 Study of ACTR707 in Combination with Rituximab in Subjects with Relapsed or Refractory CD20+ non-Hodgkin Lymphoma

Background: The Antibody-Coupled T-cell Receptor (ACTR) platform is an autologous engineered T-cell therapy that combines the cell-killing ability of T cells and the tumor-targeting ability of co-administered antibodies to exert potent antitumor immune responses. ACTR707 comprises the extracellular domain of CD16 linked to a CD3ζ signaling domain and a CD28 co-stimulatory domain. ACTR707 is in clinical development in combination with rituximab (NCT03189836) or trastuzumab (NCT03680560). Here we present clinical findings from the dose escalation phase of Study ATTCK-20-03, an ongoing, multicenter, phase 1 study of ACTR707+rituximab in subjects with relapsed or refractory (R/R) CD20+ NHL. Methods: The primary objectives of this first-in-human study are to evaluate the safety of the combination of ACTR707 and rituximab and to determine a recommended phase 2 dose (RP2D). Other objectives include evaluating antitumor activity and ACTR T-cell persistence. Subjects must have CD20+ NHL that is R/R after prior treatments, which must include anti-CD20 antibody-containing chemotherapy. Subjects receive lymphodepleting chemotherapy (cyclophosphamide and fludarabine) for 3 days, followed by rituximab and a single dose of ACTR707. Additional doses of rituximab are administered q3w until disease progression, unacceptable toxicity, or Investigator decision. The study includes a dose escalation phase (increasing doses of ACTR707 with fixed dose of rituximab at 375 mg/m2 q3w) and an expansion phase at the RP2D. Results: Six subjects received ACTR707 at Dose Level 1 (DL1; 23-38×106 ACTR+ T cells), 3 subjects at DL2 (30-50×106 ACTR+ T cells), and 5 subjects at DL3 (45-55×106 ACTR+ T cells). The majority of the subjects were diagnosed with DLBCL (93%) and had refractory disease (71%), defined as progressive disease as the best response to any prior treatment or relapse &amp;lt;1 year post autologous stem cell transplant. In DL1 through DL3, as of 27 May 2019, there were no dose-limiting toxicities, AEs of cytokine release syndrome (CRS), serious or severe neurologic AEs, or AEs leading to deaths on treatment. TEAEs reported in &amp;gt;2 subjects, regardless of causality or grade, included neutropenia, thrombocytopenia, anemia, febrile neutropenia, pyrexia, cough, constipation, diarrhea, nausea, and vomiting. SAEs considered possibly related to ACTR707 were febrile neutropenia (n=2) and cytopenia (n=1). ACTR707 expansion generally reached peak levels within 1 to 2 weeks after administration. All subjects with complete response (CR) up to 1 year had detectable ACTR at the last timepoint evaluated. Higher ACTR707 CD8:CD4 T-cell ratios were associated with clinical responses. Clinical activity was reported across DL1 through DL3, with an overall response rate of 64% including durable complete responses (CRs), with one subject in CR for 387+ days (Table 1). Conclusions: Data available from DL1 through DL3 of ACTR707+rituximab suggest that clinical responses can be achieved without severe T cell-mediated toxicities (eg, CRS and neurotoxicity) that have been reported with other autologous T-cell products. Dose escalation continues at a target dose of 80×106 ACTR+ T cells; enrollment in DL4 (n=6) was recently completed. Updated data, including identified correlates of clinical outcomes, will be presented for DL1 through DL4. Disclosures Flinn: TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; AbbVie, Seattle Genetics, TG Therapeutics, Verastem: Consultancy; TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; Acerta Pharma, Agios, Calithera Biosciences, Celgene, Constellation Pharmaceuticals, Genentech, Gilead Sciences, Incyte, Infinity Pharmaceuticals, Janssen, Karyopharm Therapeutics, Kite Pharma, Novartis, Pharmacyclics, Portola Pharmaceuticals: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding. Westin:Genentech: Other: Advisory Board, Research Funding; Janssen: Other: Advisory Board, Research Funding; Kite: Other: Advisory Board, Research Funding; Unum: Research Funding; Curis: Other: Advisory Board, Research Funding; Juno: Other: Advisory Board; MorphoSys: Other: Advisory Board; 47 Inc: Research Funding; Celgene: Other: Advisory Board, Research Funding; Novartis: Other: Advisory Board, Research Funding. Cohen:Genentech, Inc.: Consultancy, Research Funding; Takeda Pharmaceuticals North America, Inc.: Research Funding; Gilead/Kite: Consultancy; LAM Therapeutics: Research Funding; UNUM: Research Funding; Hutchison: Research Funding; Astra Zeneca: Research Funding; Lymphoma Research Foundation: Research Funding; ASH: Research Funding; Bristol-Meyers Squibb Company: Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding; Janssen Pharmaceuticals: Consultancy. Akard:Celgene: Speakers Bureau; Novartis: Speakers Bureau; Takeda: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Gilead: Speakers Bureau. Jaglowski:Juno: Consultancy, Other: advisory board; Kite: Consultancy, Other: advisory board, Research Funding; Unum Therapeutics Inc.: Research Funding; Novartis: Consultancy, Other: advisory board, Research Funding. Sachs:Unum Therapeutics Inc.: Employment. Ranger:Unum Therapeutics Inc.: Employment. Harris:Unum Therapeutics Inc.: Employment. Payumo:Unum Therapeutics Inc.: Employment. Bachanova:Celgene: Research Funding; Gamida Cell: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; GT Biopharma: Research Funding; Kite: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Novartis: Research Funding.

A Phase 1 Study of ACTR087 in Combination with Rituximab, in Subjects with Relapsed or Refractory CD20-Positive B-Cell Lymphoma

Background: The Antibody-Coupled T-cell Receptor (ACTR) platform is an autologous engineered T-cell therapy that combines the cell-killing ability of T cells and the tumor-targeting ability of co-administered antibodies to exert potent antitumor immune responses. ACTR087 comprises the extracellular domain of CD16 linked to a CD3ζ-signaling domain and a 4-1BB co-stimulatory domain. Here we present the clinical experience from Study ATTCK-20-2 (NCT02776813), a multicenter, phase 1 study of ACTR087 in combination with rituximab in subjects with relapsed or refractory (R/R) CD20+ NHL. Methods: The main objectives of this first-in-human study were to evaluate the safety and antitumor activity of ACTR087+rituximab. Other objectives included evaluating ACTR T-cell persistence and other correlative biomarkers. Subjects must have had CD20+ NHL that was R/R after prior treatments, which must have included anti-CD20 antibody-containing chemotherapy. Subjects received lymphodepleting chemotherapy (cyclophosphamide and fludarabine) for 3 days, followed by rituximab and a single dose of ACTR087. Additional doses of rituximab were administered q3w until disease progression, unacceptable toxicity, or Investigator decision. The study included a dose escalation phase (increasing doses of ACTR087) and an expansion phase (ACTR087 at the preliminary recommended phase 2 dose [RP2D]); all subjects received rituximab at a fixed dose of 375 mg/m2 q3w. Results: Two dose levels (DL) of ACTR087 were evaluated during dose escalation (n=17). The MTD was exceeded at DL2, with severe cases of cytokine release syndrome (CRS) and neurotoxicity. Statistical analysis of the relationship between non-hematologic toxicity and ACTR+ T-cell doses was retrospectively performed (two-parameter Bayesian logistic regression model) to estimate an RP2D of 35×106 ACTR+ T cells. Nine subjects enrolled in an expansion cohort and received ACTR087 at this RP2D in combination with rituximab. Among all subjects treated (n=26), the majority (69%) were diagnosed with DLBCL. Subjects had received a median of 3 (range 1-9) prior lines of therapy, with 77% having received ≥3 prior lines. ACTR087 showed dose-dependent expansion with peak levels generally observed 7 to 14 days post administration. In subjects with ongoing clinical response (CR), ACTR remained detectable through the last timepoint evaluated. Across all cohorts, Grade ≥3 TEAEs reported in &amp;gt;3 subjects regardless of causality were limited to hematologic events. Potential T cell-mediated toxicities were observed, including 4 serious cases of CRS (Gr 4 in 2 subjects, both with fatal sepsis) and 2 serious cases of neurotoxicity (1 Gr 5, 1 Gr 4 in a subject with fatal septic shock). Elevated baseline inflammatory markers (eg, ferritin, CRP) were observed in patients who developed Gr ≥3 CRS and neurotoxicity post ACTR087. Of note, severe CRS presented without fever and events occurred &amp;gt;7 days post ACTR087. Clinical activity was reported with an ORR of 50% in all dose levels tested, including durable complete responses, with one subject in CR for 869+ days (Table 1). Conclusions: ACTR087+rituximab demonstrated antitumor activity, with observed safety events that are expected with other autologous T-cell products. The time to onset and clinical presentation of severe CRS and neurotoxicity events in this study informed the safety monitoring and adverse reaction management guidance across clinical studies of ACTR T-cell products. Data from this first-in-human study of ACTR087+rituximab confirm the proof of concept and will be used to guide further development for the ACTR platform. Updated clinical data, as well as expanded biomarker correlations to efficacy and safety, will be presented. Disclosures Munoz: Pharmacyclics /Janssen: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy; Fosunkite: Speakers Bureau; AstraZeneca: Speakers Bureau; Kyowa: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene/Juno: Consultancy, Research Funding; Genentech: Consultancy, Research Funding, Speakers Bureau; Kite/Gilead: Consultancy, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy; Alexion: Consultancy; Portola: Research Funding; Incyte: Research Funding; Bayer: Consultancy, Speakers Bureau; Merck: Consultancy. Jaglowski:Kite: Consultancy, Other: advisory board, Research Funding; Novartis: Consultancy, Other: advisory board, Research Funding; Unum Therapeutics Inc.: Research Funding; Juno: Consultancy, Other: advisory board. Isufi:Celgene: Consultancy; Novartis: Consultancy; Astra Zeneca: Consultancy. Stiff:Gamida-Cell: Research Funding; Incyte: Research Funding; Cellectar: Research Funding; Unum: Research Funding; Gilead/Kite Pharma: Consultancy, Honoraria, Research Funding; Amgen: Research Funding. Sachs:Unum Therapeutics Inc.: Employment. Ranger:Unum Therapeutics Inc.: Employment. Harris:Unum Therapeutics Inc.: Employment. Payumo:Unum Therapeutics Inc.: Employment. Akard:Bristol-Myers Squibb: Speakers Bureau; Gilead: Speakers Bureau; Takeda: Speakers Bureau; Novartis: Speakers Bureau; Celgene: Speakers Bureau.

Effect of Early Post Transplantation Tacrolimus Concentration on the Risk of Acute Graft-Versus-Host Disease in Allogenic Stem Cell Transplantation

Effect of Early Post Transplantation Tacrolimus Concentration on the Risk of Acute Graft-Versus-Host Disease in Allogenic Stem Cell Transplantation

A Phase II Trial of Nivolumab and Ibrutinib for Patients with Relapsed or Refractory Central Nervous System Lymphoma

Background: Central Nervous System (CNS) lymphoma is a rare and distinct subtype of diffuse large B-cell lymphoma (DLBCL). CNS lymphoma has a unique genomic profile which has similarities to the activated B-cell (ABC) subtype of DLBCL, which may speak to potential targets for therapy. These aberrancies include near uniform reliance on Toll-Like Receptor signaling, mutations of MYD88, and frequent translocation or copy number alterations of 9p24 which codes for programmed death receptor ligand 1 (PD-L1). Mutations of MYD88 may predict for response to Bruton's tyrosine kinase (BTK) inhibitors in patients with systemic DLBCL. Expression of PD1 or PD-L1, which corresponds to response with PD-targeted therapy in solid tumors, has been found on up to 90% of CNS lymphoma cases, and 60% of specimens had tumor infiltrating lymphocytes which were PD1+ (Berghoff, Clin Neuropath 2014). In addition, the majority of CNS lymphoma cases have a copy gain of 9p24.1, associated with increased expression of PD-L1 (Chapuy, Blood 2016). This suggests a potential ongoing immune reaction against CNS lymphoma, but the microenvironment and tumor conspire to render the immune response ineffective. Ibrutinib is a BTK inhibitor which is FDA approved for multiple B-cell malignancies and is known to achieve therapeutic concentration in the cerebral spinal fluid (CSF), with activity in CNS lymphoma as a single agent and in combination with other agents. Nivolumab is a PD1 inhibitor which is FDA approved for multiple malignancies, with impressive anecdotal evidence of single agent activity in CNS lymphoma. Ibrutinib and nivolumab have been combined in other studies with modest toxicities. Study Design and Methods: We are conducting a phase II, open label, single center clinical trial combining ibrutinib with nivolumab to treat patients with relapsed CNS lymphoma (NCT03770416). Patients are eligible if they have CNS lymphoma relapsed after or were refractory to at least 1 prior line of therapy with adequate organ and bone marrow function, are aged 18y or greater, have not received prior ibrutinib or PD1 inhibitor, and do not require persistent high dose steroids. The trial has two cohorts which will be sequentially enrolled. Cohort A begins with ibrutinib 560mg oral daily for a single 28-day cycle, followed by ibrutinib combined with nivolumab 240mg IV every 14 days. Cohort B begins with the ibrutinib and nivolumab combination during the first cycle. Patients who have at least a partial response at the conclusion of the planned 6 cycles of combined ibrutinib and nivolumab may continue therapy for up to 2 years total or until progression of disease or unacceptable toxicity occurs. Neurocognitive assays and patient reported outcome instruments are being utilized. The primary objective is to determine the best overall response rate during the first 24 weeks of therapy. Secondary objectives will include the response rate of ibrutinib as a lead in prior to the combination, the complete response rate, landmark survival outcomes, and the safety of the combination. Exploratory analyses include assays of the blood and CSF for ctDNA and immune profiling. The first patient was treated in February 2019, with a planned total of 40 patients to be enrolled. Disclosures Westin: MorphoSys: Other: Advisory Board; Juno: Other: Advisory Board; Novartis: Other: Advisory Board, Research Funding; Kite: Other: Advisory Board, Research Funding; Janssen: Other: Advisory Board, Research Funding; 47 Inc: Research Funding; Genentech: Other: Advisory Board, Research Funding; Curis: Other: Advisory Board, Research Funding; Celgene: Other: Advisory Board, Research Funding; Unum: Research Funding. Fowler:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Nastoupil:TG Therapeutics: Honoraria, Research Funding; Novartis: Honoraria; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Celgene: Honoraria, Research Funding; Genentech, Inc.: Honoraria, Research Funding; Spectrum: Honoraria; Bayer: Honoraria. Neelapu:Allogene: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Novartis: Consultancy; Karus: Research Funding; Celgene: Consultancy, Research Funding; Precision Biosciences: Consultancy; Cell Medica: Consultancy; Incyte: Consultancy; Acerta: Research Funding; Unum Therapeutics: Consultancy, Research Funding; Pfizer: Consultancy; BMS: Research Funding; Poseida: Research Funding; Merck: Consultancy, Research Funding; Cellectis: Research Funding. Parmar:Cellenkos Inc.: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: ibrutinib and nivolumab are not yet indicated for CNS lymphoma

Results of a Phase I Study of Obinutuzumab, Venetoclax, and Lenalidomide in Relapsed and Refractory B-Cell Non-Hodgkin Lymphoma

Results of a Phase I Study of Obinutuzumab, Venetoclax, and Lenalidomide in Relapsed and Refractory B-Cell Non-Hodgkin Lymphoma

A Comparison of Two-Year Outcomes in ZUMA-1 (Axicabtagene Ciloleucel) and SCHOLAR-1 in Patients with Refractory Large B Cell Lymphoma

A Comparison of Two-Year Outcomes in ZUMA-1 (Axicabtagene Ciloleucel) and SCHOLAR-1 in Patients with Refractory Large B Cell Lymphoma

Correlative Analyses of Patient and Clinical Characteristics Associated with Efficacy in Tisagenlecleucel-Treated Relapsed/Refractory Diffuse Large B-Cell Lymphoma Patients in the Juliet Trial

Correlative Analyses of Patient and Clinical Characteristics Associated with Efficacy in Tisagenlecleucel-Treated Relapsed/Refractory Diffuse Large B-Cell Lymphoma Patients in the Juliet Trial

CD19-Loss with Preservation of Other B Cell Lineage Features in Patients with Large B Cell Lymphoma Who Relapsed Post-Axi-Cel

CD19-Loss with Preservation of Other B Cell Lineage Features in Patients with Large B Cell Lymphoma Who Relapsed Post-Axi-Cel

Results of a Phase II Study of Obinutuzumab in Combination with Lenalidomide in Previously Untreated, High Tumor Burden Follicular Lymphoma (FL)

Results of a Phase II Study of Obinutuzumab in Combination with Lenalidomide in Previously Untreated, High Tumor Burden Follicular Lymphoma (FL)

Analysis of Factors Predictive of Risk of Transformation and Time to Transformation in Patients (pts) with Mantle Cell Lymphoma - Cohort Study of 369 Patients

Analysis of Factors Predictive of Risk of Transformation and Time to Transformation in Patients (pts) with Mantle Cell Lymphoma - Cohort Study of 369 Patients

Characteristics and Outcomes of Patients Receiving Bridging Therapy While Awaiting Manufacture of Standard of Care Axicabtagene Ciloleucel CD19 Chimeric Antigen Receptor (CAR) T-Cell Therapy for Relapsed/Refractory Large B-Cell Lymphoma: Results from the US Lymphoma CAR-T Consortium

Characteristics and Outcomes of Patients Receiving Bridging Therapy While Awaiting Manufacture of Standard of Care Axicabtagene Ciloleucel CD19 Chimeric Antigen Receptor (CAR) T-Cell Therapy for Relapsed/Refractory Large B-Cell Lymphoma: Results from the US Lymphoma CAR-T Consortium

A Multicenter Phase II Single Arm Trial of Isatuximab in Patients with High Risk Smoldering Multiple Myeloma (HRSMM)

Background High risk smoldering multiple myeloma (HRSMM), defined as having immunoparesis and at least 95% abnormal plasma cells/all plasma cells by advanced flow cytometry, has a risk of progression to multiple myeloma of about 75% after 5 years of diagnosis. These patient have no symptoms and current standard is to follow them without treatment. Isatuximab is an IgG1 monoclonal antibody that binds to CD38 highly expressed in myeloma cells. Isatuximab has activity as monotherapy (overall response rate (ORR) 35%), with lenalidomide/dexamethasone (ORR 56%) and pomalidomide/dexamethasone (ORR 62%) in relapsed MM. We designed a phase II study to test the efficacy of isatuximab in high risk smoldering myeloma. Our study is registered in clinicaltrials.gov as NCT02960555. Methods The primary endpoint of the study is the ORR of isatuximab 20 mg/kg IV days 1, 8, 15, 22 cycle 1; days 1, 15 cycles 2-6 and day 1 cycles 7-30 in high risk smoldering myeloma. 24 patients were accrued in the first stage (of maximum 61 patients). Secondary endpoints are PFS, OS, clinical benefit rate (CBR). Exploratory endpoints are quality of life analysis (QoL), MRD, molecular/immune characterization using DNA/RNA sequencing of myeloma cells and the microenvironment before and after treatment. Results 24 patients with HRSMM were accrued from 02/08/2017 until 12/21/2018 (Table 1). All patients are evaluable for response. Best responses: ORR (≥PR) 15(62.5%), CR MRD- flow at 10-5 1 (5%), VGPR 4 (17%), PR 10 (42%), minor response (MR) 4 (18%), stable disease 5 (21%); CBR (≥MR) 79%. Median number of cycles received were 11.5 (range 6-30). Five patients have stopped treatment (one has completed the study, one with heavy history of smoking was diagnosed with squamous cell cancer of the tongue, one could no longer travel to treatments due to relocation, two progressed to active multiple myeloma after 16 and 6 cycles of treatment, respectively). There have been no deaths. DNA/RNA seq is ongoing for biomarkers of response. There were 5 grade 3 severe treatment-related adverse events (RAE) which resolved to baseline: dyspnea -related to infusion reaction (n=2), headache (n=1), ANC decrease (n=1), urinary tract infection (n=1). Most common grade 1-2 related adverse events (n): nausea (7), vomit (5), WBC decrease (3), diarrhea (3), fatigue (6), headache (4), mucositis (4), myalgia (4) and infusion reaction (3). In patients with available QoL functional scores (n=9 at baseline and n=7 after 6 months of therapy), isatuximab was effective in reducing their anxiety and worry of progression to multiple myeloma. Isatuximab also improved general QoL scores by the end of cycle 6 of treatment which were now comparable to those in the general population (Figure 1). Conclusion Isatuximab is very well tolerated, results in high response rates in HRSMM and has the potential to change the natural history of this disease. In ongoing QoL analysis, initial data shows improvement in QoL and decreased cancer worry after isatuximab treatment. Immune-genomic analysis is ongoing and may identify patients that benefit the most from treatment. Disclosures Manasanch: celgene: Honoraria; merck: Research Funding; quest diagnostics: Research Funding; sanofi: Research Funding; BMS: Honoraria; Sanofi: Honoraria. Jagannath:Multiple Myeloma Research Foundation: Speakers Bureau; BMS: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Medicom: Speakers Bureau; Merck: Consultancy. Lee:Daiichi Sankyo: Research Funding; Celgene: Consultancy, Research Funding; GlaxoSmithKline plc: Research Funding; Sanofi: Consultancy; Takeda: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Patel:Poseida Therapeutics, Cellectis, Abbvie: Research Funding; Oncopeptides, Nektar, Precision Biosciences, BMS: Consultancy; Takeda, Celgene, Janssen: Consultancy, Research Funding. Kaufman:Janssen: Other: travel/lodging, Research Funding. Thomas:Xencor: Research Funding; BMS: Research Funding; Celgene: Research Funding; Amgen: Research Funding. Mailankody:Takeda Oncology: Research Funding; Juno: Research Funding; Celgene: Research Funding; Janssen: Research Funding; CME activity by Physician Education Resource: Honoraria. Lendvai:Janssen: Employment. Neelapu:Acerta: Research Funding; Celgene: Consultancy, Research Funding; BMS: Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Incyte: Consultancy; Merck: Consultancy, Research Funding; Allogene: Consultancy; Cellectis: Research Funding; Poseida: Research Funding; Karus: Research Funding; Pfizer: Consultancy; Unum Therapeutics: Consultancy, Research Funding; Novartis: Consultancy; Precision Biosciences: Consultancy; Cell Medica: Consultancy. Orlowski:Poseida Therapeutics, Inc.: Research Funding. Landgren:Sanofi: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Theradex: Other: IDMC; Abbvie: Membership on an entity's Board of Directors or advisory committees; Merck: Other: IDMC. OffLabel Disclosure: Isatuximab for the treatment of smoldering myeloma

A Phase I/II Study of Lenalidomide Plus Obinutuzumab in Relapsed Indolent Lymphoma

Background: Patients with advanced indolent non-Hodgkin lymphoma (iNHL) can develop chemoresistance and most relapse following standard therapy. Although multiple treatment options exist, most are associated with short remission or intolerable side effects. Lenalidomide activates NK cells ± T cells and leads to in vivo expansion of immune effector cells in NHL models. The combination of rituximab and lenalidomide (R2) in relapsed iNHL is highly active and was recently approved. Obinutuzumab is a glycosylated type II anti-CD20 molecule with enhanced affinity for the FcγRIIIa receptors leading to improved ADCC. The primary objective of this phase I/II study was to determine the maximum tolerated dose (MTD), safety, and efficacy of lenalidomide and obinutuzumab in relapsed indolent lymphoma. Methods: Patients with relapsed small lymphocytic lymphoma (SLL), marginal zone, and follicular lymphoma (gr 1-3a) were eligible. Patients enrolled in three predefined dose cohorts of lenalidomide (10mg,15mg, 20mg) given on days 2-22 of a 28 day cycle. Obinutuzumab was given at a fixed dose (1000mg) IV on days 1,8,15 and 22 of cycle 1 and day 1 of subsequent cycles for 6 cycles. The combination was given for up to 12 cycles in responding pts. Antihistamines were given in pts who developed rash. Prophylactic growth factor was not allowed. In the absence of progression or toxicity, single agent obinutuzumab was continued every 2 months for maximum of 30 months on study. Traditional 3+3 dose escalation was used with dose limiting toxicities (DLT) assessed during cycle 1. Once the MTD was established, 60 additional patients were enrolled in the phase II portion of the study. Adverse events were graded using CTCAE version 4.03. Results: 66 pts were enrolled between May 2014 until March 2019, and all are eligible for safety and response assessment. No DLTs were observed in dose escalation, and 60 pts were enrolled in the phase II portion of the study at 20mg of lenalidomide daily. Histologies included follicular lymphoma (FL) n=57, marginal zone n=4, SLL n=5. The median age was 64 (36-81), with 2 (1-5) median prior lines of treatment. For 53% of pts, the combination represented the third or greater line of treatment. The overall response (OR) rate for all pts was 98% with 72% attaining a complete response (CR). Eighteen pts (27%) had a partial response, and stable disease was noted in 1 (2%). At a median follow up of 17 months, 14 pts have progressed, with an estimated 24mo progression-free survival (PFS) of 73% (57-83% 95% CI). The estimated 24 mo PFS for ≥ third line pts was 63%. Twenty five pts (38%) remain on treatment and 95% remain alive at last follow up. The most common grade ≥ 3 non-hematologic toxicities included fatigue (5 pts), rash (4 pts), and cough (3 pts). Grade ≥3 neutropenia and thrombocytopenia occurred in 11 (17%) and 7 (11%) pts respectively. Two pts stopped treatment due to adverse events, including 1 transient bradycardia and 1 grade 3 fatigue. Conclusion: The combination of 20 mg of lenalidomide and 1000mg obinutuzumab is safe and effective in patients with relapsed indolent lymphoma. Adverse events appeared similar to our prior experience with lenalidomide and rituximab and were generally well tolerated. Overall response rates were high, with many pts achieving prolonged remission, including pts who had relapsed after 2 or more lines of prior therapy. Validation studies in the frontline and salvage setting are ongoing. Disclosures Fowler: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; ABBVIE: Membership on an entity's Board of Directors or advisory committees, Research Funding. Nastoupil:TG Therapeutics: Honoraria, Research Funding; Novartis: Honoraria; Janssen: Honoraria, Research Funding; Spectrum: Honoraria; Gilead: Honoraria; Genentech, Inc.: Honoraria, Research Funding; Bayer: Honoraria; Celgene: Honoraria, Research Funding. Westin:Novartis: Other: Advisory Board, Research Funding; Celgene: Other: Advisory Board, Research Funding; Juno: Other: Advisory Board; Janssen: Other: Advisory Board, Research Funding; Kite: Other: Advisory Board, Research Funding; Unum: Research Funding; MorphoSys: Other: Advisory Board; Genentech: Other: Advisory Board, Research Funding; Curis: Other: Advisory Board, Research Funding; 47 Inc: Research Funding. Neelapu:Precision Biosciences: Consultancy; Merck: Consultancy, Research Funding; Cellectis: Research Funding; Novartis: Consultancy; BMS: Research Funding; Karus: Research Funding; Acerta: Research Funding; Poseida: Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Incyte: Consultancy; Celgene: Consultancy, Research Funding; Unum Therapeutics: Consultancy, Research Funding; Allogene: Consultancy; Pfizer: Consultancy; Cell Medica: Consultancy.

Results of a First in Human, Dose Ascending, Phase I Study Examining the Safety and Tolerability of KA2237, an Oral PI3K p110β/δ Inhibitor in Patients with Relapsed/Refractory (R/R) B-Cell Lymphoma

Results of a First in Human, Dose Ascending, Phase I Study Examining the Safety and Tolerability of KA2237, an Oral PI3K p110β/δ Inhibitor in Patients with Relapsed/Refractory (R/R) B-Cell Lymphoma