Refractory CD20 Research Articles

Clinical interaction between dexamethasone and aprepitant in chemotherapy for lymphoma.

Aprepitant (Apr) is an effective antiemetic agent for chemotherapy-induced nausea and vomiting (CINV). Current CINV guidelines recommend the antiemetic combination of a 5-HT3 receptor antagonist, Apr, and dexamethasone (Dex) for highly emetogenic chemotherapies. Apr inhibits CYP3A4 dose-dependently. Since Dex is metabolized by CYP3A4, the combined use of Apr and Dex inhibits Dex metabolism. CINV guidelines therefore recommend dose-reduction of Dex when Apr and Dex are used together. However, there is some controversy over whether or not Dex should be reduced when administered as an antitumor agent for lymphoid malignancies. We retrospectively compared the antitumor effect of Dex-containing chemotherapy in which Dex is administered at the usual dose without Apr (group A) or administered at a half-dose in combination with Apr (group B). We analyzed 62 consecutive patients with refractory or relapsed CD20 + B cell lymphoma who received R-DHAP therapy in our hospital, including 29 and 33 cases in groups A and B, respectively. The response rate at the end of the first course of R-DHAP was 62.1% and 54.5%, respectively (P = 0.61). As another endpoint to evaluate the effect of Dex, group B tended to show greater suppression of the lymphocyte count (P = 0.05). Therefore, decreasing the dose of Dex by half appeared to be reasonable when combined with Apr.

64 - CD30-Directed CAR-T Cells Co-Expressing CCR4 in Relapsed/ Refractory Hodgkin Lymphoma and CD30+ Cutaneous T Cell Lymphoma

64 - CD30-Directed CAR-T Cells Co-Expressing CCR4 in Relapsed/ Refractory Hodgkin Lymphoma and CD30+ Cutaneous T Cell Lymphoma

A Phase 1 Trial of Adct-602, a CD22 Targeting Antibody Drug Conjugate Bound to PBD Toxin in Adult Patients with Relapsed or Refractory CD22+ B-Cell Acute Lymphoblastic Leukemia

A Phase 1 Trial of Adct-602, a CD22 Targeting Antibody Drug Conjugate Bound to PBD Toxin in Adult Patients with Relapsed or Refractory CD22+ B-Cell Acute Lymphoblastic Leukemia

A Phase 1 Dose Escalation Study of Igm-2323, a Novel Anti-CD20 x Anti-CD3 IgM T Cell Engager (TCE) in Patients with Advanced B-Cell Malignancies

A Phase 1 Dose Escalation Study of Igm-2323, a Novel Anti-CD20 x Anti-CD3 IgM T Cell Engager (TCE) in Patients with Advanced B-Cell Malignancies

A Phase I Open Label Dose Escalation Study of MB-CART19.1 in Relapsed and Refractory CD19+ B Cell Malignancies, Interim Preliminary Results in Pediatric ALL, Adult ALL Including CLL Cohorts

A Phase I Open Label Dose Escalation Study of MB-CART19.1 in Relapsed and Refractory CD19+ B Cell Malignancies, Interim Preliminary Results in Pediatric ALL, Adult ALL Including CLL Cohorts

Is Hospital Exemption an Alternative or a Bridge to European Medicines Agency for Developing Academic Chimeric Antigen Receptor T-Cell in Europe? Our Experience with ARI-0001.

The hospital exemption (HE) allows for the use of advanced therapy medicinal products (ATMPs) next to marketing authorization (MA), but under special conditions. The HE is only applicable to individual patients treated in the hospital setting and it is limited to member states of the European Union (EU); HE is mainly conceded to the academic centers that developed the ATMP, being granted by the national competent authority (NCA), which, in the case of Spain, is the Spanish Agency of Medicines and Medical Devices (AEMPS). The HE follows strict standards of traceability, pharmacovigilance, and quality. In February 2021, our ATMP ARI-0001, a new autologous chimeric antigen receptor (CAR) targeting CD19, was approved by AEMPS under HE for patients >25 years with relapsed or refractory CD19+ acute lymphoblastic leukemia. This authorization was a first step in the development of, and access to, academic CAR T cell products in the EU. The fact that HE is limited to a specific country and hospital, the need of continuous evaluation by the NCA, and the potential future overlap with other centrally approved ATMPs, suggest that the HE could be used as an intermediate step before obtaining a centralized MA by the European Medicines Agency.

Dose escalation of subcutaneous epcoritamab in patients with relapsed or refractory B-cell non-Hodgkin lymphoma: an open-label, phase 1/2 study

Patients with relapsed or refractory B-cell non-Hodgkin lymphoma have few treatment options. We aimed to establish the safety and recommended phase 2 dose of epcoritamab, a novel bispecific antibody that targets CD3 and CD20 and induces T-cell-mediated cytotoxic activity against CD20+ malignant B cells. For the dose-escalation part of this phase 1/2 study, we enrolled adults (aged ≥18 years) with relapsed or refractory CD20+ B-cell non-Hodgkin lymphoma at ten sites across four countries (Denmark, the Netherlands, the UK, and Spain). Eligible patients received priming and intermediate doses followed by full doses of subcutaneous epcoritamab administered in 28-day cycles; each subsequent cohort involved escalation of the priming, intermediate, or full dose (0·0128-60 mg). The primary objectives were to determine the maximum tolerated dose and the recommended phase 2 dose. Safety, antitumour activity, pharmacokinetics, and immune biomarkers were also assessed. This study is registered with ClinicalTrials.gov, NCT03625037, with the dose-expansion part ongoing. Between June 26, 2018, and July 14, 2020, we enrolled 73 patients with relapsed, progressive, or refractory CD20+ mature B-cell non-Hodgkin lymphoma. 68 patients received escalating full doses (0·0128-60 mg) of subcutaneous epcoritamab. No dose-limiting toxic effects were observed, and the maximum tolerated dose was not reached; the full dose of 48 mg was identified as the recommended phase 2 dose. All 68 patients received at least one dose of epcoritamab and were included in safety analyses: common adverse events were pyrexia (47 patients [69%]), primarily associated with cytokine release syndrome (CRS; 40 [59%], all grade 1-2), and injection site reactions (32 [47%]; 31 grade 1). There were no grade 3 or higher CRS events. No discontinuations occurred due to treatment-related adverse events or treatment-related deaths. Overall response rate in patients with relapsed or refractory diffuse large B-cell lymphoma was 68% (95% CI 45-86), with 45% achieving a complete response at full doses of 12-60 mg. At 48 mg, the overall response rate was 88% (47-100), with 38% achieving a complete response. Patients with relapsed or refractory follicular lymphoma had an overall response rate of 90% (55-100), with 50% achieving a complete response at full doses of 0·76-48 mg. Epcoritamab induced robust and sustained B-cell depletion, and CD4+ and CD8+ T-cell activation and expansion, with modest increases in cytokine levels. Single-agent subcutaneous epcoritamab for treatment of patients with relapsed or refractory B-cell non-Hodgkin lymphoma merits investigation in ongoing phase 2 and phase 3 studies. Genmab and AbbVie.

Phase II Trial to Evaluate the Efficacy and Safety of the Combination of Obinutuzumab and Bendamustine Treatment in Patients (Pts) with Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)

Introduction: The use of combined rituximab (R)-bendamustine(B) has shown to be effective in terms of overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) in pts with relapsed/refractory CLL. Based on the enhanced in vitro and in vivo anti-CLL activity of obinutuzumab compared to rituximab, we designed this phase II study to evaluate the efficacy of obinutuzumab(Obi) with B in patients (pts) with relapsed or refractory CLL.Methods Between April 2014 and April 2017, 72 adult pts with relapsed or refractory CD20+ CLL (according to NCI criteria) and active disease (IWCLL 2008) were included in this prospective, multicenter, non-comparative, phase II study. Pts received up to six-28-day cycles of treatment consisting of obinutuzumab (1000 mg) given by intravenous (IV) infusion on Days (D) 1, 8, and 15 of Cycle 1 and on D1 of subsequent cycles, and B (70 mg/m2) by IV infusion on D2 and 3 of Cycle 1 and on D1 and 2 of subsequent cycles. The primary endpoint was ORR (by IWCLL 2008); secondary endpoints included best RR, OS and PFS, duration of response and minimal residual disease (MRD) rate detected by multicolor flow cytometry (sensitivity: 1 CLL cell in 10-4). We present the results of an interim analysis at 6 months of last Obi-B cycle with the data cut-off date of 25th of April of 2017.Results. Pts were mostly male (66.7%), with a median age of 67.9 (61.6-72.7) years and ECOG 0 in 62.5% of them. Rai clinical stage was low/intermediate (0-II) in 52.8% pts and high-risk (III-IV) in 47.2% pts. Forty eight pts relapsed after an FC+/-R (58.3%) or B-R (8.3%) therapy and 7(9.7%) pts were refractory to last immunochemotherapy. Expression of CD38 (>30%), CD49D (>20%), ZAP-70 was seen in 15.3%, 55.6%, and 39.4% of pts respectively, and unmutated immunoglobulin heavy chain gene (IGHV) status in 75.0% of pts. Genetic abnormalities detected by FISH and Sanger sequencing were: del13q(44.4%), trisomy 12(18.05%), del11q/ATMmutation(43.05%), del17p/p53mutation (26.3%), mutations of BIRC3(4.1%), SF3B1(9.7%) and NOTCH1(23.6%). Out of 72 enrolled pts, 80.6% and 79.2% completed 6 cycles of treatment with Obi and B respectively. Median (range) treatment duration was 4.9 (4.6-5.1) months. Obi doses were modified in 75% of pts (premature discontinuations: 4%; infusion rate reduction: 15.9%; temporarily interruptions: 77.8%). B was modified in 52.8% of pts (premature discontinuations: 7.2%; temporarily interruptions: 55.4%; dose reductions: 30.1; dose reduction rate: 2.4%). On an intent to treat analysis, 70(97.2%) pts were evaluable for efficacy according to protocol, the ORR was 81.4 % (CR 35.7%, CRi 7.1% and PR 38.6%), PD (2.9%) and SD (5.7%). In the 7 pts with refractory CLL, the ORR was 71.4% (CR 42.9%, CRi 14.3% and PR 14.3%) and SD 28.6%. After a median follow-up of 13.7 months, the median PFS was 27.0 months (figure 1). The median time to retreatment 33.8 months (figure 2). Significant differences were found in the PFS according to MRD status in Bone Marrow (Category: Cat.0: MRD level<0.01, 30.2 months, Cat. 1: MRD between 0.01-0.1: 21.6 months and Cat. 2:MRD>0.1: 12.1 months; p<0.001) and in the PFS regarding the IGHV mutation status (unmutated, 24.1 months vs mutated, median non-reached; p<0.05). The presence of p53 and ATM disruption did not have a significant impact on response, perhaps because of the high RR (81.4%). Sixty-three pts (87.5%) reported at least 1 toxicity, being the most common grade 3/4 neutropenia (51.4%) and thrombocytopenia (19.5%). In total, 82 SAEs or AESI were reported in 34(53.9%) pts. The discontinuation rate due to AEs was 18.1%. Two deaths occurred due to toxicities, acute myeloid leukemia and septic shock.Conclusions This interim analysis anticipates that the combination of obinutuzumab with Bendamustine is feasible, effective with an ORR of 81.4% and manageable in relapsed/refractory CLL. Achievement of MRD negativity in the bone marrow of pts treated with Obinutuzumab+Bendamustine seems associated with a longer PFS regardless of genetic abnormalities. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Shortening the Time to Manufacture CAR+ T Cells with Sleeping Beauty System Supports T-Cell Engraftment and Anti-Tumor Effects in Patients with Refractory CD19+ Tumors

▪BACKGROUND:. We have previously reported the first human application of non-viral gene transfer using the Sleeping Beauty (SB) transposon/transposase system to stably express a 2nd generation CD19-specific chimeric antigen receptor (CAR) which resulted in survival benefits for recipients of autologous and allogeneic T cells delivered as adjuvant immunotherapy after hematopoietic stem cell transplantation (HSCT) (J Clin Invest. 2016 126(9):3363-76). This CAR (CD19RCD28) used a Fc-based extracellular stalk and T cells were generated after 28 days (4 “stimulations”) of recursive culture on activating and propagating cells (AaPC). To further improve persistence we modified this CAR construct and shortened the ex vivo time to produce clinical-grade T cells.METHODS: A new Phase 1 clinical trial (NCT02529813) at MD Anderson Cancer Center enrollspatients with a history of CD19+ lymphoid malignancy with active disease for dose escalation of SB-modified autologous T cells which were infused following lymphodepletion chemotherapy, starting at ≤105 (dose level, DL -1), >105 but ≤106 (dose level, DL 1) and then escalating in cohorts of 3 to the dose of >108 but ≤109 CD3+CAR+ cells/kg (DL 4). The CD19-specific CAR employed a revised stalk derived from CD8, and as per CD19RCD28, signaled through chimeric CD28 and CD3-z endodomains (designated CD19RCD8CD28). SB-derived DNA plasmids coding for CAR (transposon) and transposase were electro-transferred into peripheral blood mononuclear cells and subsequently co-cultured every ~7 days on irradiated K-562-derived CD19+ AaPC in the presence of IL-2 and IL-21 to selectively propagate CAR+ T cells. During dose escalation, T-cell manufacturing time was shortened by reducing the number of additions of AaPC from four to two stimulations. The final product met release criteria and was thawed prior to infusion.RESULTS: In this ongoing trial, 6 patients with median age 41 years (range 29-69 years) with active CD19+ lymphoid malignancy (CLL, n=1; ALL, n= 4; DLBCL, n=1) have been dosed so far (DL -1, n=1; DL 1, n=3; DL 2, n=2). All had refractory/relapsed disease with four having prior allogeneic HSCT. Median CAR expression upon infusion was 86% (range 19%-97%). No DLTs or CD19 related SAEs were observed. Only grade 1 cytokine release syndrome (CRS) was noted in 2 patients. The median follow-up for patients is 3 months (range 0.3-13.8 months). Anti-tumor effects were noted and infused T cells could be detected by flow cytometry and PCR (Figure).CONCLUSIONS: These initial data describing the infusion of SB-modified T cells with a revised extracellular domain and under reduced manufacturing time results in the detection of genetically modified T cells and anti-tumor effects in patients with relapsed/refractory ALL apparently without clinically-significant CRS. These data support advancing an approach for non-viral gene transfer to administer CAR+ T cells, and working toward even shorter manufacturing times.Figure: Persistence of circulating CD19-specific CAR+ T cells in patients after single infusion of SB-modified T cells, as determined by ddPCR. Circles represent a patient at given time point, short horizontal lines represent mean, and the continuous line connecting the means describes the trend. [Display omitted] DisclosuresHuls:Former employee of Intrexon: Employment. Smith:Ziopharm: Employment. De Groot:Ziopharm: Employment. Kantarjian:Amgen: Research Funding; ARIAD: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Bristol-Meyers Squibb: Research Funding; Delta-Fly Pharma: Research Funding. Cooper:Miltenyi Biotec: Honoraria; Ampliphi Biosciences: Equity Ownership; Procter & Gamble: Equity Ownership; Organovo Holdings: Equity Ownership; Targazyme, Inc.: Equity Ownership; Argos Therapeutics: Equity Ownership; Intrexon Corporation: Equity Ownership, Patents & Royalties; Immatics: Equity Ownership, Patents & Royalties, Research Funding; Sangamo Biosciences: Patents & Royalties; Ziopharm: Employment, Equity Ownership, Research Funding; Ferring: Consultancy.

Preliminary Results of UCART19, an Allogeneic Anti-CD19 CAR T-Cell Product in a First-in-Human Trial (PALL) in Pediatric Patients with CD19+ Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia

▪BackgroundUCART19 is a genetically modified T-cell product manufactured from non-HLA matched healthy donor cells and aims to provide a ready to use, off-the-shelf allogeneic engineered CAR T-cell product. Lentiviral-transduced CAR T-cells express (1) an anti-CD19 CAR (anti-CD19 scFv- 41BB- CD3ζ), and (2) an RQR8 “safety switch” that is intended to allow targeted elimination of RQR8+ cells by rituximab. UCART19 has been additionally modified to disrupt the T-cell receptor alpha constant (TRAC) and CD52 genes. We previously reported the success of this approach in two infants treated under compassionate use who achieved molecular remissions ahead of allogeneic transplantation and remain in remission with follow-up for 18 and 24 months. Here we describe preliminary results of a Phase 1 trial of UCART19 in pediatric patients (pts) with high risk relapsed refractory (R/R) CD19+ B-ALL and no therapeutic options.MethodsThis study evaluates the safety and tolerability of a fixed dose (2x107 total cells or 1.1 to 2.3x106 cells/kg) of UCART19 and its ability to achieve molecular remission at day (D) 28 to enable allogeneic stem cell transplantation (allo-SCT). Up to 10 subjects with R/R B-ALL aged between 6 months and < 18 years, with morphologically confirmed CD19+ B-ALL or an MRD load ≥ 1x10-3 are eligible. The lymphodepletion regimen combines cyclophosphamide and fludarabine with or without alemtuzumab (FC or FCA). UCART19 is administered thereafter (Day 0) as a single dose infusion. If the patient achieves molecular remission, allo-SCT is scheduled within 6 to 12 weeks (wks) after infusion, and trial period continues for a further 12 months before entry into a long-term follow-up study.ResultsAs of 24 June 2017, 5 children (3 males and 2 females), including two infant leukaemias, aged between 8 months and 16.4 years had been enrolled and treated. Four pts had received 3 or more previous lines of treatment and 2 had undergone a previous allo-SCT. All patients were unsuitable for or had failed generation of an autologous CAR T-cell product. All had received debulking chemotherapy and/or inotuzumab ozogamicin therapy before UCART19. All pts received lymphodepletion with FCA. No immediate infusion related reaction (IRR) related to UCART19 were reported. All pts experienced reversible cytokine release syndrome (CRS) (1 grade (G) 1, 3 G2, 1 G3), with one child requiring 2 doses of tocilizumab. Time to onset of first CRS symptoms was between D4 and D8. Two pts presented mild neurological symptoms that recovered (within 1 to 3 days) without treatment. Acute skin GvHD G1 was reported in two pts (one with biopsy confirmation) and both recovered with topical steroids. Four children experienced viral complications (CMV, ADV, BK, metapneumovirus) related to lymphodepletion, and all experienced neutropenia, which was prolonged in 2/5 pts. By D28-42, 5/5 pts had achieved complete remission with incomplete blood count recovery albeit with hypoplastic marrows (all patients were MRD negative by flow cytometry or qPCR ). UCART19 were detectable from D7 to at least D28 in all subjects by qPCR and/or flow cytometry and by molecular signatures of T-cell donor chimerism. All proceeded to conditioned allo-SCT between 7 to 9 weeks after UCART19 infusion, with no gene-modified cells detectable thereafter. Two children relapsed 3 months after transplantation (one CD19- and one CD19+) and died 7 and 8 months after UCART19 infusion respectively. One subject died in remission from transplant related complications including thrombotic microangiopathy and BK haemorrhagic cystitis and nephritis. Two subjects remain in molecular remission 2 and 2.5 months post-transplant.ConclusionPreliminary results of this first-in-human trial of UCART19 treatment in a high risk R/R B-ALL pediatric population revealed no unexpected toxicities. GvHD seen in 2 patients was mild and self-limiting. Lymphodepletion-related viral complications and persisting neutropenia were encountered. All five treated subjects were rendered either flow or PCR MRD negative enabling allogeneic transplantation to proceed. The trial is ongoing in the UK and further data may be presented (NCT02808442) . DisclosuresQasim:Autolus Ltd: Consultancy, Equity Ownership; Miltenyi: Research Funding; Orchard Therapeutics: Consultancy, Equity Ownership; Servier: Research Funding; Bellicum: Research Funding; NIHR: Research Funding; Cellectis: Research Funding. Lucchini:Alexion: Membership on an entity's Board of Directors or advisory committees. Zinaï:Servier: Employment. Binlich:Servier: Employment. Dupouy:Servier: Employment. Pauly:Servier: Employment. Balandraud:Servier: Employment. Dubois:Servier: Employment. Konto:Bristol-Myers Squibb: Employment, Equity Ownership; Pfizer: Employment, Equity Ownership. Patel:Pfizer: Employment, Equity Ownership. Veys:Bellicum: Research Funding; Servier: Research Funding.

Radiographic and High-Throughput Sequencing (HTS)-Based Response Assessment after Brentuximab Vedotin (BV) Plus Ifosfamide, Carboplatin, and Etoposide (ICE) for Relapsed/Refractory (Rel/Ref) Classical Hodgkin Lymphoma (cHL): Updated Results of a Phase I/II Trial

BACKGROUNDThe likelihood of long-term remission following autologous stem cell transplant (ASCT) for rel/ref cHL is predicted by response to pre-ASCT salvage therapy (Blood 2012;119:1665-70). Salvage regimens incorporating the anti-CD30 antibody-drug conjugate BV, administered sequentially and concurrently with chemotherapy, show promise in improving positron emission tomography (PET)-negative complete remission (CR) rates, transplant eligibility, and outcomes (Lancet Oncol 2015;16:284-92; ASH 2015, #293; ASH 2016, #1109; ASH 2016, #1834). While pre-ASCT PET is a strong predictor of outcome, novel HTS-based assays in development imply greater sensitivity than imaging and a potential role in management and surveillance of lymphomas. Here, we report updated clinical results from our ongoing phase I/II trial (#NCT02227199) in the context of HTS-based detection of HL pre- and post-therapy, as well as circulating cytokine and tumor microenvironment markers. METHODSPatients (pts) ≥ 18 years old with first relapse or primary refractory CD30+ cHL were eligible for this IRB-approved prospective clinical trial. Treatment included BV on Days 1 and 8 at either 1.2 or 1.5 mg/kg (based on 3+3 dose-escalation schema; capped at 150 mg), ifosfamide and mesna 5 g/m2 each on Day 2, carboplatin AUC 5 (capped at 800 mg) on Day 2, and etoposide 100 mg/m2 daily on Days 1-3. 2 21-day cycles were given with G-CSF support. BV 1.5 mg/kg was selected as the phase II dose based on reported dose escalation data (ASH 2016, #1834). PET was performed after Cycle 2, with response assigned per Cheson 2007. Peripheral blood (PB) pre- and post-treatment, stem cell (PBSC) product, and (when available) archived formalin-fixed paraffin-embedded tissue (FFPET) from presentation and relapse were collected for correlative studies. DNA for HTS was extracted and analyzed by Adaptive Biotechnologies similar to that described previously (Clin Cancer Res 2014;20:4540-8). Pre-treatment PB cytokine levels were measured by Luminex. Immunohistochemistry (IHC) on FFPET identified components of inflammatory microenvironment. RESULTSTo date, 24 pts have enrolled and 23 are evaluable (1 withdrew consent after 1 cycle). 15 (65%) pts are female. Median age at enrollment was 30 (range, 20-60), with 7 (30%) age ≥ 45. 9 (39%) had advanced-stage disease at initial diagnosis. 14 (61%) did not obtain CR with first-line therapy, all but 1 of which was ABVD-based (the exception received Stanford V). 6 (26%) received prior radiation.Of 23 evaluable pts, 20 (87%) achieved a PET CR by investigator review, while 16 (70%) were in PET CR by central independent review. Of the 4 with discrepant results between investigator and central review, 2 were adjudicated as CR by a 3rd independent reviewer, and 2 were sent for biopsy of residual lesion: 1 biopsy was negative, and 1 noted resolution by imaging guidance so biopsy was aborted. 19 of 22 pts (86%) with adequate follow-up have undergone ASCT. 1 pt in CR after BV-ICE has since relapsed (5%), and no deaths have occurred. The toxicity profile remains similar to that reported previously: 11 (48%) pts experienced Grade 3-4 non-heme toxicity, with sepsis/neutropenic fever (4), hyperglycemia (2), and elevated ALT (2) being the most common; 7 pts (30%) developed neuropathy: 4 Grade 1, 2 Grade 2, and 1 Grade 3; only 1 pt (4%) discontinued study therapy due to toxicity (Grade 3 neuropathy).21 patients had samples tested for disease-specific clonal sequence by HTS. A clone was detectable in PB pre-treatment in only 1 (5%). Post-treatment, none of the PB or PBSC had a detectable clone. Proportions of CD68+ macrophages, granzyme+ cytotoxic cells, and CD20+ B cells by IHC of FFPET from either initial diagnosis or at relapse/enrollment were similar between those who achieved CR and those who did not, as were circulating levels of MIG, HGF, IL2Ra, IL6, and PDL1. CONCLUSIONSBV at a dose of 1.5 mg/kg on Days 1 and 8 per cycle of ICE results in high CR rates, is generally well tolerated, and warrants further investigation in pts with rel/ref cHL. Contrary to previous data (Br J Haematol, 2015;169:689-93), HTS was not able to reliably identify disease-specific clone in PB and thus may not be a useful tool in cHL at present. Inflammatory cell composition and selected serum cytokine levels were not predictive of response to BV-ICE. Enrollment is ongoing, and updated clinical and correlative data will be presented at the meeting. DisclosuresSmith:Dohme Corp: Research Funding; Acerta: Research Funding; Sharp: Research Funding; Janssen: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Merck: Research Funding; Genentech: Research Funding; Portola Pharmaceuticals: Research Funding; Seattle Genetics: Research Funding. Gopal:Seattle Genetics: Consultancy, Research Funding.

A Pilot Study of Weekly Brentuximab Vedotin in Patients with CD30+ Malignancies Resistant to Every 3 Week Brentuximab Vedotin

Background:Brentuximab vedotin (BV) is effective in treating of relapsed/refractory CD30 positive malignancies, such as classical Hodgkin lymphoma (CHL) and systemic anaplastic large cell lymphoma (ALCL). BV combines an anti-CD30 monoclonal antibody with a potent anti-microtubule agent, Monomethyl auristatin E (MMAE), disrupting the cell cycle of CD30 positive cells. Patients (pts) with relapsed/refractory CHL and systemic ALCL have shown promising overall response rates (ORR) with BV, but most patients will eventually suffer progressive disease (PD). The mechanism of resistance to BV remains unclear, however, most lymphomas with PD following BV still demonstrate CD30 expression suggesting that it may remain a viable target. Prior clinical data indicate that weekly BV dosing given on Days 1, 8 and 15 of a 28 day cycle was tolerable, had an ORR of 59% and a higher complete remission rate than was seen in a similar phase I trial of 21-day dosing of BV. We, thus, hypothesized that patients with CD30-positive lymphomas who progressed on standard BV dosing may still respond to weekly BV dosing and tested this in a prospective phase II trial. We also quantified CD30 expression to evaluate the impact of BV on CD30 expression and the impact of CD30 on response to BV, and assessed T and NK cell infiltrates for correlation with response.Methods:Eligible pts were age >18 or older with relapsed or refractory CD30 positive lymphoma who had progressed during or achieved less than a partial response following a minimum of 2 cycles of BV. Key inclusion criteria included documented expression of CD30 on tumor cells following the last dose of prior BV, as well as adequate marrow, hepatic and renal function and no major infections. Key exclusion criteria were ECOG > 2, prior transplant within 100 days, radioimmunotherapy within 12 weeks, active CNS involvement, and pre-existing neuropathy > NCI-CTCAE Grade 2 (or > Grade 1 if secondary to prior BV). Each cycle consisted of BV at 1.2 mg/kg (capped at 120mg) given over 30 minutes on Days 1, 8 and 15 every 28 days. Patients with stable disease or better could remain on therapy for up to 4 cycles. CD30 expression was quantified using multiparameter flow cytometry to identify the Hodgkin-Reed-Sternberg (HRS) cells.Results:Eight (8) pts enrolled in the study. The median age was 42 (27-68). The pts were heavily pretreated (median 6 prior lines of treatment) and 63% had undergone autologous transplant (Table 1). Histologies included CHL (7) and ALK-negative systemic ALCL (1). Pts received between 2 to 16 (median 5) prior cycles of Q3 week BV prior to enrolling in the study. All patients suffered eventual progressive disease (PD) on Q3 week BV, though 3 had a transient prior partial response (PR). Weekly BV was well tolerated with only one grade 3 event (hypokalemia). Neuropathy was seen in 5 (63%) pts: 3 Grade 1, 2 Grade 2 resulting in one treatment discontinuation. Two pts completed all 4 BV cycles on study; both had progressive disease after the 4th cycle. Of the 6 pts who terminated the study early, the majority (67%) did so due to progressive disease. One pt had a partial response to BV after 3 cycles (with a 50% decrease in size of target nodes compared to baseline). Reduction in target lesions were seen in 5/7 (71%) response-evaluable patients (Figure 1). The overall response rate (ORR) of 13% triggered the protocol-defined early stopping rule. None of the screened patients were found to have lost CD30 expression following prior BV, however expression only ranged from dim to intermediate by IHC. CD30 surface density was quantified in paired pre and post BV samples from 3 patients and did not show a significant change or correlation with response. NK and T cell infiltrates were not correlated with response.Conclusions:Pts with BV-refractory CD30 positive malignancies can safely receive weekly BV at 1.2 mg/kg dosing given on Days 1, 8 and 15 of a 28-day cycle. Even though a majority demonstrated reduction in target lesions, the response rate was low. Alterations in CD30 density on HRS cells was not observed following BV when quantified by flow cytometry. Elucidation of tumor- and immune-related mechanisms of BV resistance is needed, as BV is poised for increased use earlier in the course of therapy for HL and ALCL. [Display omitted] DisclosuresSmith:Portola Pharmaceuticals: Research Funding; Seattle Genetics: Research Funding; Janssen: Research Funding; Acerta: Research Funding; Genentech: Research Funding; Sharp: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Dohme Corp: Research Funding; Merck: Research Funding. Gopal:Seattle Genetics: Consultancy, Research Funding.

Proceedings From the First International Workshop at Sidra Medicine: "Engineered Immune Cells in Cancer Immunotherapy (EICCI): From Discovery to Off-the-Shelf Development", 15th-16th February 2019, Doha, Qatar.

The progress in the isolation and characterization of tumor antigen (TA)-specific T lymphocytes and in the genetic modification of immune cells allowed the clinical development of adoptive cell therapy (ACT). Several clinical studies highlighted the striking clinical activity of T cells engineered to express either Chimeric Antigen (CAR) or T Cell (TCR) Receptors to target molecularly defined antigens expressed on tumor cells. The breakthrough of immunotherapy is represented by the approval of CAR-T cells specific for advanced or refractory CD19+ B cell malignancies by both the Food and Drug Administration (FDA) and the European Medicinal Agency (EMA). Moreover, advances in the manufacturing and gene editing of engineered immune cells contributed to the selection of drug products with desired phenotype, refined specificity and decreased toxicity. An important step toward the optimization of CAR-T cell therapy is the development of “off-the shelf” T cell products that allow to reduce the complexity and the costs of the manufacturing and to render these drugs available for a broad number of cancer patients. The Engineered Immune Cells in Cancer Immunotherapy (EICCI) workshop hosted in Doha, Qatar, renowned experts, from both academia and industry, to present and discuss the progress on both pre-clinical and clinical development of genetically modified immune cells, including advances in the “off-the-shelf” manufacturing. These experts have addressed also organizational needs and hurdles for the clinical grade production and application of these biological drugs.

Anti-CD19 Chimeric Antigen Receptor T Cell Treatment of Relapsed /Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Resistant to Bruton's Tyrosine Kinase (BTK) Inhibitor

CASE PRESENTATION: A 68-year-old male was diagnosed with CLL/SLL in November 2007. Bone marrow asp/bx: 36.5% lymphocytes, 78% CD19, 65% ATM (11q22 deleted) positive cells, 13.5% D13S25 (13q14.3 deleted). On December 10, 2009, the patient took FCR scheme for five cycles, followed by FR scheme for one cycle, and then a month of Chlorambucil. On September 5, 2013, the patient took BR scheme for four cycles with no effect. From March 2015 to Feb 2016, 420 mg of Ibrutinib was administered daily. On January 15, 2016, the patient developed swollen lymph nodes in his right neck with intermittent lumps, fever and nausea. He was admitted into the hospital at Feb 2, 2016. Test results: multiple swollen superficial lymph nodes over the body, with the biggest measuring 60×30mm on the right neck, with no tenderness. Supplementary tests: peripheral white blood cells (WBC) 11.94×10E9/L, lymphocyte 7.5×10E9/L, CD19 cells 6.73×10E9/L, bone marrow lymphocyte 62%, peripheral blood lymphocyte 52%. Immunophenotype: CD5, CD19, CD20dim, CD23, CD11b dim, HLA-DR expression, visible CD5+CD19+ cell clusters, and visible immunoglobulin cKappa with restricted expression. On March 10, 2016, peripheral blood platelet 60 × 10E9/L, CD19 cells 1.94×10E9/L, lactate dehydrogenase 460U/L, FER 115.6ng/ml, hepatitis B virus carrier. Diagnosis: CLL/SLL IV stage, ATM (11q22) deletion, D13S25 (13q14. 3) positive, CD19 positive. Relapse of CLL/SLL occurred again after four months and at this stage the patient was considered for therapy in a clinical trial of CD19-specific chimeric antigen receptor (CAR-) T cell therapy. Ethical approval and informed consent were obtained for anti-CD19 CAR T Cell treatment of ibrutinib resistance in relapsed/refractory CLL/SLL. We infused autologous T cells transduced with a CAR T 19 retroviral vector with CLL/SLL at doses of 3.3 × 10E8 CART19 cells on Mar. 16 2016. Patients were monitored for responses, toxic effects, and the expansion and persistence of circulating CART19 cells. After CART19 cells were infused, the patient experienced chills, fever, headache, weak, anorexia, nausea, shortness of breath, chest tightness, heart palpitation, hypotension and shock for 9 days. The serum levels of IFN-Υ were at their highest at day 7 after CAR T cells infusion. Serum interleukin 6 (IL-6) was at 680pg/ml and CD3+ cells were 97.5%, CD8+ cells 72.8% (18.7-32.8%), FER was 1529.5ng/ml (Normal No. 22-322ng/ml) 14 days after CAR-T cell infusion. The serum levels of IL-6 were at their highest at day14. The patient was diagnosed as having cytokine release syndrome. After the patient took the anti-IL-6R antibody and anti-TNF antibody, he began to recover gradually. Enlarge lymph nodes shrunk after being infused with CART19 cells for 7 days. The peripheral blood CD19 B lymphocytes were 0 on day 14 after infused with CAR T19 cells. Q-PCR was used to detect the amount of the peripheral blood CART19 cells, which stood at 5485 copies/μl, 924 copies/μl, 191 copies/μl respectively 2 weeks, 6 weeks and 3 months after infusing with CART19 cells. The peripheral blood CART 19 cells were not detectable 4 months after infusing with CART19 cells until present. The lymphadenopathy was decreased gradually after 14 days of infusion. The MRI test showed that lymphadenopathy reduced markedly or disappeared after 6 months of infusion. ATM (11q22 deleted) negative, D13S25 (13q14.3 deleted) negative. After treatment with CAR T 19 cell therapy for 53 months, the patient remained disease-free, the patient's lymph nodes, lymphocytes and I mmunoglobulins were normal. CONCLUSIONS : Cancer immunotherapy as a method of cancer treatment is the most effective after conventional treatments such as radiotherapy, chemotherapy, and surgery. For BTK Inhibitor resistance in relapsed and refractory CD19+ CLL/SLL, CD19 is a favorable target, because the expression of CD19 is limited to B cells and not present in other tissues or cells. Currently, the efficacy of this treatment in treating CLL/SLL remains to be seen. The effects of chemotherapy on the patient's B cell lymphoma are negligible, due to the fact that his CLL/SLL have become relapsed and refractory. As a result we chose the CAR T19 cell therapy genetic engineering technique as a method of treatment, to which the patient has responded well. Therefor, CAR T cell technology overcome the limitations of existing cancer therapies and has great potential for development and application. Disclosures No relevant conflicts of interest to declare.

Title: Clinical and Biological Evaluation of the Novel CD30/CD16A Tetravalent Bispecific Antibody (AFM13) in Relapsed or Refractory CD30-Positive Lymphoma with Cutaneous Presentation: A Biomarker Phase Ib/IIa Study (NCT03192202)

Introduction: Natural Killer cells (NK) play an important role in tumor immune-surveillance. The innate cell engager AFM13 is a CD30/CD16A targeting high affinity bispecific tetravalent antibody that engages and activates NK. This study evaluates AFM13's clinical and immunological activity. It examines the immunologic changes in the tumor and in peripheral blood (PB) as a function of the dose and method of administration of AFM13. Methods: Subjects with relapsed or refractory CD30 expressing lymphoma with cutaneous involvement were recruited into 4 cohorts: 1.5 mg/kg IV weekly, 7 mg/kg IV weekly, 7 mg/kg continuous intravenous infusion (CIVI) over 5 days weekly and 200mg IV weekly. Each cohort consisted of 3 subjects with 3 additional subjects in cohort 4. Subjects received 8 weeks of therapy for up to 2 cycles. Response assessment was performed on week 11 of each cycle by mSWAT, photography, PET imaging and PB flow cytometry. A second cycle was administered if there was no progression. Subjects underwent skin biopsies and PB immunologic studies as follows: pretreatment, day 5, week 4 and week 8 of therapy. Biopsies were analyzed and evaluated by a pathologist and IHC image analyzer. PB samples were analyzed by flow cytometry. Results: Fourteen subjects were accrued. The median number of prior therapies was 4 (1-11) and 4 subjects had progressed on brentuximab vedotin. The disease etiologies, treatment emergent toxicities and response by cohort are presented in Table 1. An objective response rate of 40% was observed in the study. In the PB, flow cytometry revealed a decrease in circulating NK (CD16/56+ CD3- CD19- lymphocytes) during therapy with post therapy recovery. The activation marker CD69 on NK increased in responders (R) compared to non-responders (NR). Similarly, tumor biopsies in R showed increased infiltration and activation of CD56+ NK as opposed to NR (Figure 1). NK cytotoxicity through the expression of Granzyme B was seen in R vs. NR. Flow quantitation of circulating CD4+ CD25+ T cells (Tregs) showed a decrease in R vs. NR. Conclusions: AFM13 demonstrated a high ORR of 40% among a population of heavily pretreated subjects with CD30 positive lymphoproliferative T-cell malignancies. AFM13 exhibited activity post brentuximab vedotin failure. In addition, biological changes in NK infiltration and activation in the PB and tissue biopsy correlated with response. These data are the first to demonstrate that innate cell engagers modulate NK and T cell populations in the peripheral blood and tumor from patients and to determine that such changes are associated with patient benefit. Disclosures Sawas: Roche: Current equity holder in publicly-traded company; Affimed: Research Funding; Daiichi Sankyo: Speakers Bureau; Seattle Genetics: Speakers Bureau; Gilead: Speakers Bureau; Flatiron Health: Current Employment. Chen:Affimed: Research Funding. Lipschitz:Affimed: Research Funding. Rodig:Bristol Myers Squibb: Research Funding; Merck: Research Funding; Affimed: Research Funding; KITE/Gilead: Research Funding; Immunitas: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees.

Dose-Dense Brentuximab Vedotin Plus Ifosfamide, Carboplatin, and Etoposide (ICE) Is Highly Active for Second Line Treatment in Relapsed/Refractory Classical Hodgkin Lymphoma: Final Results of a Phase I/II Study

Dose-Dense Brentuximab Vedotin Plus Ifosfamide, Carboplatin, and Etoposide (ICE) Is Highly Active for Second Line Treatment in Relapsed/Refractory Classical Hodgkin Lymphoma: Final Results of a Phase I/II Study

Abstract PO-63: A phase 2a open-label study of MT-3724, a novel CD20-targeting engineered toxin body, in combination with lenalidomide (LEN) in subjects with relapsed or refractory B-cell non-Hodgkin lymphoma (NHL)

Abstract Background: Engineered toxin bodies (ETBs) are a distinct class of targeted immunotoxins in development by Molecular Templates as anticancer therapeutics. ETBs have a novel mechanism of action that drives a potent and targeted response mediated by antibody-like binding, cellular internalization, and enzymatic ribosomal inhibition via the delivery of a Shiga-like toxin subunit A (SLTA). MT-3724 comprises an anti-CD20 single chain variable fragment genetically fused to SLTA with an approximate molecular weight of 55 kDa and is being developed for the treatment of relapsed or refractory diffuse large B-cell lymphoma (r/rDLBCL). MT-3724 is currently being studied in three ongoing phase 1/2 studies for r/rDLBCL. Methods: MT-3724 is being evaluated in this phase 2a study (NCT03645395) in combination with LEN in adult patients with histologically confirmed, relapsed, or refractory CD20+ B-cell NHL. The primary objectives of this study are to determine the safety and tolerability, including the maximum tolerated dose (MTD), of MT-3724+LEN. Secondary objectives include pharmacokinetics, pharmacodynamics, immunogenicity, and tumor response. The study is being conducted in two parts. Part 1 includes MT-3724 dose escalation over 5 dose cohorts according to the modified 3+3 design and will include up to 24 subjects with CD20+ NHL. Part 2 is designed to assess the safety and tolerability of MT-3724+LEN in the MTD Expansion Cohort, where the dose declared as MTD of MT-3724 in Part 1 will be given in combination with LEN in up to 40 subjects with CD20+ r/rDLBCL. Eligible subjects must have received at least one approved therapy for NHL and must have measurable disease by Lugano criteria. Subjects who have progressed following CAR T-cell therapy, autologous or allogeneic stem cell transplant are also eligible. Serum rituximab level must be negative (&amp;lt;500 ng/mL) at screening because it competes with MT-3724 for binding to CD20. In the first 2 dose cohorts (10 and 25 ug/kg/dose) of Part 1, subjects received MT-3724 IV infusions over 1 hour three times weekly for 2 weeks and LEN (20 mg daily) on Days 1-21 of each 28-day treatment cycle for Cycles 1 and 2. In subsequent cycles, MT-3724 was administered once weekly with continued LEN dosing on Days 1-21. Because of 2 dose-limiting toxicities (grade 2 capillary leak syndrome) in Cohort 2, the dose in Cohort 3 was reduced to 20 ug/kg/dose. The protocol was amended so that in future Cohorts 4 and 5 (25 and 50 ug/kg/dose), MT-3724 will be dosed biweekly for 2 weeks for Cycles 1 and 2 and then once weekly for subsequent cycles. The study is recruiting subjects at multiple study centers. Citation Format: Jason Tache, Deborah A. Katz, Amitabha Mazumder, David Peace, Christine Burnett, Thomas Strack, Elizabeth Bay, Roger Waltzman, Seung Lee. A phase 2a open-label study of MT-3724, a novel CD20-targeting engineered toxin body, in combination with lenalidomide (LEN) in subjects with relapsed or refractory B-cell non-Hodgkin lymphoma (NHL) [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr PO-63.

Chimeric Antigen Receptor, Teamwork, Education, Assessment, and Management (CAR-TEAM): A Simulation-Based Inter-professional Education (IPE) Intervention for Management of CAR Toxicities.

Chimeric antigen receptor (CAR) therapies such as tisagenlecleucel, indicated for children and young adults with relapsed and/or refractory CD19+ acute lymphoblastic leukemia (ALL), have been associated with striking treatment outcomes and overall survival. Yet, they are also associated with unique and potentially life-threatening complications. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS) are generally reversible complications of CAR therapies, but many patients may require critical care support especially if they are not promptly recognized and appropriately managed by frontline healthcare staff. As CAR therapies become more widely available, it is important that inter-professional staff members be aware of general principles regarding diagnosis and management. We hypothesized that an inter-professional education (IPE) simulation-based education intervention (CAR-TEAM) would improve knowledge base and confidence regarding complications of CAR therapies among inter-professional staff. Here, we demonstrate that following CAR-TEAM training, >90% of participants demonstrated knowledge proficiency and confidence in the IPE content area. CAR-TEAM training may serve as an important tool to establish initial and continued competency among sites introducing CAR therapies.

SWOG 1312 Final Results: A Phase 1 Trial of Inotuzumab in Combination with CVP (Cyclophosphamide, Vincristine, Prednisone) for Relapsed/ Refractory CD22+ Acute Leukemia

SWOG 1312 Final Results: A Phase 1 Trial of Inotuzumab in Combination with CVP (Cyclophosphamide, Vincristine, Prednisone) for Relapsed/ Refractory CD22+ Acute Leukemia

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.