Faculty Bibliography

Introduction: IGM-2323 is the first engineered high-affinity, high-avidity bispecific IgM monoclonal antibody TCE to be tested in the clinic. It has 10 binding domains for CD20 and a single binding domain for CD3 and is designed to bind irreversibly to CD20-high and low-expressing cells with more physiologic stimulation to T cells, which may mitigate cytokine release syndrome (CRS)-related toxicity and broaden the therapeutic window. IGM-2323 may act by multiple mechanisms: T-cell dependent cytotoxicity, complement dependent cytotoxicity, and enhanced immune modulation via IFNgamma-dominant cytokine stimulation. This phase 1 study is exploring the safety and activity of IGM-2323 using a dose titration schedule intended to optimize repeatable immune stimulation while minimizing toxicity.
Method(s): This first-in-human Phase 1 study is a global, multicenter, open-label, dose escalation evaluating safety, tolerability, PK, and preliminary efficacy (NCT04082936). Adults with relapsed or refractory CD20 ⁺ B-cell NHL with >= 2 prior systemic therapies, adequate organ function, and ECOG 0-1 are eligible. IGM-2323 is given IV on Days 1, 8, and 15 of 21-day cycles until disease progression or unacceptable toxicity. Treatment can continue beyond progression if the patient (pt) has benefitted from treatment and intra-patient dose escalation is allowed. This study also utilizes a dose titration scheme where a starting dose is given on Day 1, then higher subsequent doses...
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Despite recent therapeutic advances in the management of non-Hodgkin lymphoma (NHL), up to 50% of patients with diffuse large B-cell lymphoma (DLBCL) relapse after first line therapy, and for DLBCL patients who relapse within 12 months after subsequent stem cell transplant (SCT), the median overall survival (OS) is 6.3 months. Recently, chimeric antigen receptor (CAR) T-cell therapy has shown remarkable activity in relapsed DLBCL with complete response (CR) rate of 40% and 54% for the two of the FDA-approved CAR T-cell products, tisagenlecleucel and axicabtagene ciloleucel, respectively. However, at a median follow-up of 18 months, only 36% of patients treated with tisagenlecleucel remained in CR; with longer follow-up for axicabtagene ciloleucel the median progression free survival (PFS) was 5.9 months. Immune escape and immune evasion are primary mechanisms of CAR-T resistance; clearly improvements are needed to increase response rate and cure. While CRISPR-based loss-of-function screens have shown promise for high-throughput identification of genes that modulate T-cell response, these methods have been limited thus far to negative regulators of T-cell functions, and raise safety concerns due to the permanent nature of genome modification. Here we identify positive T-cell regulators via overexpression of ~12,000 barcoded human open reading frames (ORFs). Using this genome-scale ORF screen, we found modulator genes which increased primary human CD4+ and CD8+ T-cell proliferation, including activation markers like CD25 and CD40L, and secretion of key cytokines like interleukin-2 and interferon-gamma. In addition, we developed a single-cell genomics method (OverCITE-seq) for high-throughput quantification of the transcriptome and surface proteome in ORF-engineered T-cells. The top-ranked ORF, lymphotoxin beta receptor (LTBR), is typically expressed in a subset of myeloid cells but absent in lymphocytes. When expressed in T-cells, LTBR induces a profound transcriptional remodelling, resulting in increased resistance to exhaustion and activation-induced apoptosis, as well as upregulation of a plethora of proinflammatory cytokines, co-stimulatory molecules and antigen presentation machinery. In order to investigate the mechanism of action of LTBR, we developed an epistasis assay which allows for simultaneous gene knockout and LTBR overexpression in primary T cells. Thus, LTBR appears to induce both canonical and non-canonical NFkB pathways - but the phenotype observed in T cells is dependent only on the former. Finally, we co-expressed several top-ranked genes, including LTBR, with FDA approved CD19-targeting CARs utilizing either 4-1BB or CD28 co-stimulatory domains. In line with previous results, co-expression of top-ranked ORFs increased proinflammatory cytokine secretion and cytotoxicity against CD19+ positive cancer cell lines. This functional improvement was also observed when top-ranked ORFs and CARs were delivered to T cells isolated from DLBCL patients as shown in Figure 1. Our results provide several strategies for improving next generation CAR T-cell therapies via induction of new synthetic cell programs which may optimize immune activation and enhance the efficacy of these important therapies, a high priority for patients with relapsed and refractory DLBCL and other lymphomas. [Formula presented] Disclosures: Mimitou: Immunai: Current Employment. Smibert: Immunai: Current Employment. Diefenbach: Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; IMab: Research Funding; Gilead: Current equity holder in publicly-traded company; Celgene: Research Funding; AbbVie: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Merck Sharp & Dohme: Consultancy, Honoraria, Research Funding; IGM Biosciences: Research Funding; Morphosys: Consultancy, Honoraria, Research Funding; MEI: Consultancy, Research Funding; Perlmutter Cancer Center at NYU Langone Health: Current Employment; Incyte: Research Funding; Trillium: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Genentech, Inc./ F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding. Sanjana: Qiagen: Consultancy; Vertex: Consultancy.
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Antibody responses serve as the primary protection against SARS-CoV-2 infection through neutralization of viral entry into cells. We have developed a two-dimensional multiplex bead binding assay (2D-MBBA) that quantifies multiple antibody isotypes against multiple antigens from a single measurement. Here, we applied our assay to profile IgG, IgM and IgA levels against the spike antigen, its receptor-binding domain and natural and designed mutants. Machine learning algorithms trained on the 2D-MBBA data substantially improve the prediction of neutralization capacity against the authentic SARS-CoV-2 virus of serum samples of convalescent patients. The algorithms also helped identify a set of antibody isotypeâ€"antigen datasets that contributed to the prediction, which included those targeting regions outside the receptor-binding interface of the spike protein. We applied the assay to profile samples from vaccinated, immune-compromised patients, which revealed differences in the antibody profiles between convalescent and vaccinated samples. Our approach can rapidly provide deep antibody profiles and neutralization prediction from essentially a drop of blood without the need of BSL-3 access and provides insights into the nature of neutralizing antibodies. It may be further developed for evaluating neutralizing capacity for new variants and future pathogens.

BACKGROUND:Obinutuzumab with polatuzumab vedotin or lenalidomide showed tolerability and activity in phase 1b/2 trials that recruited patients with relapsed or refractory follicular lymphoma. We aimed to examine whether the novel polatuzumab vedotin-obinutuzumab-lenalidomide (Pola-G-Len) combination might enhance antitumour response in patients with relapsed or refractory follicular lymphoma. METHODS:This multicentre, single-arm phase 1b/2 study tested Pola-G-Len in patients with relapsed or refractory follicular lymphoma, and polatuzumab vedotin in combination with rituximab and lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma. Here we report the results from the cohort of patients with follicular lymphoma. The trial was done in 18 cancer centres across three countries (Spain, UK, and USA). Patients (≥18 years old) with CD20-positive relapsed or refractory follicular lymphoma (excluding grade 3b) and Eastern Cooperative Oncology Group performance status of 2 or less who had previously received anti-CD20-containing chemotherapy were eligible for inclusion. During the dose-escalation phase, patients received six 28-day cycles of induction treatment with intravenous obinutuzumab 1000 mg (all cohorts), and intravenous polatuzumab vedotin and oral lenalidomide (Celgene, Summit, NJ, USA) in the following doses: 1·4 mg/kg polatuzumab vedotin and 10 mg lenalidomide (cohort 1); 1·8 mg/kg polatuzumab vedotin and 10 mg lenalidomide (cohort 2); 1·4 mg/kg polatuzumab vedotin and 15 mg lenalidomide (cohort 3); 1·8 mg/kg polatuzumab vedotin and 15 mg lenalidomide (cohort 4); 1·4 mg/kg polatuzumab vedotin and 20 mg lenalidomide (cohort 5); and 1·8 mg/kg polatuzumab vedotin and 20 mg lenalidomide (cohort 6). Polatuzumab vedotin was administered on day 1, lenalidomide on days 1-21, and obinutuzumab on days 1, 8, and 15 of cycle one and day 1 of cycles two to six of each 28-day cycle. During phase 2 (dose expansion phase), patients received six cycles of induction with Pola-G-Len at the recommended phase 2 dose established during dose-escalation. Patients who had a response or stable disease at the end of induction were eligible to enter the maintenance phase, in which they received obinutuzumab for 24 months at 1000 mg on day 1 of every other 28-day cycle for a total of 12 doses, and lenalidomide for 12 months at 10 mg on days 1-21 of each 28-day cycle for a maximum of 12 cycles. The primary activity endpoint was complete response at the end of induction. Adverse events were monitored throughout the study. The primary safety objective was to determine the maximum tolerated dose of Pola-G-Len. Analyses were in the safety population, which included all patients that received at least one dose of any of the component drugs (ie, all patients who entered the induction phases in both the escalation and expansion phases), and activity-evaluable population, which included all patients who received at least one dose of any of the component drugs at the recommended phase 2 dose (ie, all patients who received the recommended phase 2 dose in the dose escalation investigation and all patients who entered induction in the dose expansion investigation). This ongoing trial is registered at ClinicalTrials.gov, NCT02600897. FINDINGS/RESULTS:Between March 24, 2016, and August 23, 2018, 56 patients (33 [59%] men and 23 [41%] women; 49 [88%] non-Hispanic or Latino) were enrolled. Two of four patients in cohort 2 reported dose-limiting toxicity events during dose escalation (one patient had grade 4 amylase and lipase elevation and one patient had grade 4 neutropenia and grade 3 thrombocytopenia), and there were no dose-limiting toxicities observed in cohorts 3 or 5; therefore, the recommended phase 2 dose for the dose-expansion was 1·4 mg/kg polatuzumab vedotin plus 20 mg lenalidomide. 46 (82%) patients were included in the activity-evaluable population. After a median follow up of 26·7 months (IQR 22·2-31·3) the objective response rate was 76% (90% CI 64-86) and complete response rate was 63% (90 CI 50-75). After a median follow-up of 27·0 months (IQR 18·7-34·0), the most common grade 3-4 adverse events were neutropenia (31 [55%] of 56 patients) and thrombocytopenia (14 [25%] patients). 61 serious adverse events were reported in 35 (63%) patients; the most common of which were febrile neutropenia (five [9%] patients; a sixth patient had febrile neutropenia, but this was not considered serious by the investigator), pneumonia (four [7%] patients), and pyrexia (four [7%] patients). One fatal adverse event (grade 5 septic shock) occurred in a patient who had discontinued study treatment due to disease progression and had initiated a new anti-lymphoma tyrosine kinase inhibitor treatment. This was not considered related to study treatment by the investigator. INTERPRETATION/CONCLUSIONS:Pola-G-Len showed high complete response rates, although it did not reached the prespecified threshold for activity, in patients who were heavily pretreated with refractory follicular lymphoma. Our findings compare favourably with available therapies and support future investigation of Pola-G-Len in a larger patient population. FUNDING/BACKGROUND:Genentech/F Hoffmann-La Roche.

Background: Mosunetuzumab (M), a full-length, humanized, IgG1 bispecific antibody targeting CD20 and CD3, has shown promising efficacy and safety as monotherapy for relapsed/refractory (R/R) B-cell non-Hodgkin's lymphoma (B-NHL) (NCT02500407; Assouline, et al. ASH 2020). The combination of M with the anti-CD79b antibody-drug conjugate, polatuzumab vedotin (Pola), showed synergistic anti-lymphoma activity in a mouse xenograft model. These data supported a Phase Ib/II, open-label, multicenter trial of M-Pola for R/R B-NHL (GO40516, NCT03671018).
Aim(s): To present early clinical data from the Phase Ib cohort of the GO40516 study.
Method(s): Patients (pts) with R/R follicular lymphoma (FL; grade [Gr] 1-3a) or aggressive NHL (aNHL), including de novo diffuse large B-cell lymphoma (DLBCL), transformed FL (trFL) and FL Gr 3b (FL3b), received Cycle (C) 1 step-up doses of M on Day (D) 1 (1mg) and D8 (2mg), the target dose on C1D15, then continued at the target dose on C2D1 onwards. M was given every 21 days for eight cycles (or 17 cycles if stable disease or a partial response after C8). Pola (1.8mg/kg) was given with M on D1 of each cycle for six cycles.
Result(s): As of November 17, 2020, 22 pts had received M-Pola (M target doses: 9mg, n=7; 20mg, n=3; 40mg, n=6; 60mg [with D1 dose of 30mg from C3 onwards], n=6). Pts had DLBCL (n=12), FL (n=3), FL3b (n=3) and trFL (n=4). Pt characteristics include: median age of 70 (38-81) years; median of 3 (1-10) prior lines of therapy; 7 (32%) pts had prior chimeric antigen-receptor T-cell (CAR-T) therapy; 17 (77%) and 19 (86%) pts had disease refractory to last prior therapy and prior anti-CD20 therapy, respectively. Median follow-up duration was 9.6 (0.7-23.7) months. The most frequent treatment-related adverse events (AEs) were neutropenia (45.4%), fatigue, nausea and diarrhea (all 36.4%). Cytokine release syndrome (CRS) was observed in 2 pts (9.1%; both Gr 1 by American Society for Transplantation and Cellular Therapy 2019 criteria). One dose-limiting toxicity (Gr 3 new onset atrial fibrillation) was observed in the 40mg cohort. The maximum tolerated dose was not exceeded. The most common Gr >=3 and serious AEs were both neutropenia, observed in 8 (36.4%) and 3 (13.6%) pts, respectively. Two (9.3%) Gr 5 AEs occurred: sudden cardiac death (n=1) and respiratory failure (n=1); neither was deemed treatment related. No immune effector cell-associated neurotoxicity was observed. The Table shows preliminary efficacy data. Summary/Conclusion: These data indicate that M-Pola has an acceptable safety profile, with no Gr >=2 CRS observed, and promising efficacy in pts with R/R NHL with predominantly aggressive disease. The Phase II expansion cohort in R/R DLBCL is ongoing, with no mandatory hospitalization required. . 2021 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2021 ASCO Annual Meeting. All rights reserved

Context: Follicular lymphoma (FL) often presents with recurrent relapses. Treatment options for patients (pts) with FL who have received >=2 prior lines of therapy are limited, and prognosis is poor. The safety and efficacy of mosunetuzumab, a full-length, fully humanized IgG1 CD20/CD3 bispecific antibody is currently being investigated in an ongoing open-label, multicenter, Phase I/Ib, dose-escalation and expansion trial in relapsed/refractory (R/R) B-cell lymphoma (GO29781; NCT02500407).
Objective(s): To present updated data from the R/R FL cohort.
Method(s): Pts received intravenous mosunetuzumab step-up doses in cycle (C) 1, days (D) 1 and 8, then the target dose on D15 and D1 of each subsequent 21-day cycle (Group B); treatment continued for <=17 cycles.
Result(s): As of January 21, 2020, mosunetuzumab 0.4/1.0/2.8 mg to 1/2/13.5 mg (C1D1/8/15 dose levels) was given to 62 pts with FL who received >=2 prior systemic therapies. Pts had a median age of 59 (27-85) years, median number of 3 (2-11) prior therapies; 33 pts (53%) were double refractory, 30 (48%) had progression of disease within 24 months of first-line treatment (POD24), and four (6%) received prior chimeric antigen receptor T-cell (CAR-T) therapy. Overall response rate (ORR) and CR rate were 68% and 50%, respectively. In high-risk pts, consistent CR rates were observed: 55% (18/33) in pts with double refractory disease, 53% (16/30) in pts who had POD24, 78% (7/9) in pts with PI3Ki refractory FL, and 50% (2/4) in those who received prior CAR-T therapy. Twenty-six pts with a CR (74%) remained in remission (median time on study: 14.4 months). In responders (n=42), median duration of response was 20.4 months (95% CI: 11.7-not reached), and median progression-free survival was 11.8 months (95% CI: 7.3-21.9). Adverse events (AEs) and serious AEs were reported in 60 (97%) and 22 pts (35%), respectively. The most common grade (Gr) >=3 AEs included hypophosphatemia (23%) and neutropenia (21%). Fourteen pts (23%) experienced CRS1; events were mostly Gr 1 or 2, reversible, and occurred largely during C1.
Conclusion(s): A high CR rate, durable responses, and a manageable safety profile were observed with mosunetuzumab monotherapy in heavily pre-treated pts with FL, including high-risk pts.
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Context: Mosunetuzumab (Mosun), a full-length, humanized, IgG1 CD20xCD3 bispecific antibody, showed promising efficacy/safety for R/R B-NHL (NCT02500407; Assouline, et al. ASH 2020). Mosun combined with the anti-CD79b antibody-drug conjugate Pola showed synergistic anti-lymphoma activity in a mouse xenograft model, supporting the Phase Ib/II, open-label, multicenter trial of Mosun-Pola for R/R B-NHL (GO40516, NCT03671018).
Objective(s): To present early clinical data from the Phase Ib cohort of GO40516.
Method(s): Patients with R/R follicular lymphoma (FL, grade 1-3a) or aggressive NHL (aNHL), including de novo diffuse large B-cell lymphoma (DLBCL), transformed FL (trFL), and grade 3b FL (FL3b), received Cycle (C)1 step-up doses of Mosun on Day (D)1 (1 mg) and D8 (2 mg), and target dose on C1D15, continuing from C2D1. Mosun was given every 21 days for eight cycles, continuing for <=17 cycles. Pola (1.8 mg/kg) was administered with Mosun on D1 of six cycles.
Result(s): As of November 17, 2020, 22 patients received Mosun-Pola (Mosun target doses: 9 mg, n=7; 20 mg, n=3; 40 mg, n=6; 60 mg [D1 dose 30 mg from C3 onward], n=6). Patients had DLBCL (n=12), FL (n=3), FL3b (n=3), and trFL (n=4). Median age: 70 (38-81) years; median 3 (1-10) prior lines of therapy; prior chimeric antigen receptor T-cell (CAR-T) therapy (n=7; 32%). Median follow-up duration: 9.6 (0.7-23.7) months. Most frequent treatment-related adverse events (AEs): neutropenia (45.4%), fatigue, nausea, and diarrhea (all 36.4%). Cytokine release syndrome was observed in two patients (9.1%; both grade 1 [Lee, et al. Biol Blood Marrow Transplant 2019]). One dose-limiting toxicity (grade 3 new-onset atrial fibrillation) was observed in the 40 mg cohort; maximum tolerated dose not exceeded. Most common grade >=3 AE: neutropenia (n=8; 36.4%). Two (9.3%) grade 5 AEs occurred (sudden cardiac death [n=1]); respiratory failure [n=1]); neither was deemed treatment-related. Complete responses were achieved with Mosun-Pola in patients with R/R aNHL (n=9; 47.4%), prior CAR-T therapy (n=2; 28.6%) and FL (n=3; 100%).
Conclusion(s): These data indicate that Mosun-Pola has an acceptable safety profile and shows promising efficacy in patients with predominantly aggressive R/R NHL. The Phase II expansion cohort in patients with R/R DLBCL is ongoing, with no requirement for mandatory hospitalization.
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Central nervous system (CNS) involvement in Burkitt lymphoma (BL) poses a major therapeutic challenge, and the relative ability of contemporary regimens to treat CNS involvement remains uncertain. We described prognostic significance of CNS involvement and incidence of CNS recurrence/progression after contemporary immunochemotherapy using real-world clinicopathologic data on adults with BL diagnosed between 2009 and 2018 across 30 US institutions. We examined associations between baseline CNS involvement, patient characteristics, complete response (CR) rates, and survival. We also examined risk factors for CNS recurrence. Nineteen percent (120/641) of patients (age 18-88 years) had CNS involvement. It was independently associated with HIV infection, poor performance status, involvement of ≥2 extranodal sites, or bone marrow involvement. First-line regimen selection was unaffected by CNS involvement (P=0.93). Patients with CNS disease had significantly lower rates of CR (59% versus 77% without; P<0.001), worse 3-year progression-free survival (adjusted hazard ratio [aHR], 1.53, 95% confidence interval [CI], 1.14-2.06, P=0.004) and overall survival (aHR, 1.62, 95%CI, 1.18-2.22, P=0.003). The 3-year cumulative incidence of CNS recurrence was 6% (95%CI, 4-8%). It was significantly lower among patients receiving other regimens (CODOX-M/IVAC, 4%, or hyperCVAD/MA, 3%) compared with DA-EPOCH-R (13%; adjusted sub-HR, 4.38, 95%CI, 2.16-8.87, P<0.001). Baseline CNS involvement in BL is relatively common and portends inferior prognosis independent of first-line regimen selection. In real-world practice, regimens with highly CNS-penetrant intravenous systemic agents were associated with a lower risk of CNS recurrence. This finding may be influenced by observed suboptimal adherence to the strict CNS staging and intrathecal therapy procedures incorporated in DA-EPOCH-R.