Blogs

The MagnetisMM-1 trial: A BCMA-targeting bispecific T cell engager for relapsed or refractory multiple myeloma

158. Elranatamab, a BCMA Targeted T-Cell Engaging Bispecific Antibody, Induces Durable Clinical and Molecular Responses for Patients with Relapsed or Refractory Multiple Myeloma

Noopur Raje (Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, United States) presented results from MagnetisMM-1, an ongoing Phase 1 first-in-human study elranatamab, a humanized bispecific antibody targeting BCMA on myeloma cells and CD3 on T cells, for relapsed or refractory multiple myeloma (RRMM). MagnetisMM-1 enrolled 55 patients to receive elranatamab monotherapy composed of 20% Black/African American patients, and 7.3% of patients were of Asian descent. 26.3% of patients (n=13) received prior BCMA-targeted therapy, either BCMA-targeting antibody-drug conjugates or CAR-T cells. 87.3% of patients experienced cytokine release syndrome (CRS) at either Grade 1 or 2; no Grade 3 or 4 CRS events were reported. The frequency of CRS was mitigated to 67% with the addition of step-up priming and premedication. Soluble BCMA levels decreased over time in responding patients. The overall response rate was 64%, with 38% of patients achieving complete response (CR) or stringent CR. Of the patient population receiving prior BCMA-directed therapy, 54% (7/13) achieved a response. Among responding patients, the median duration of response was 17.1 months. Of the 13 evaluable patients with confirmed CR or better, 100% achieved minimal residual disease (MRD) negativity (performed by next-generation sequencing at a sensitivity of 1 x 10^-5), 62% of these patients were MRD-negative for over six months, and 31% were MRD-negative for over 12 months. Median progression-free survival for all patients was 11.8 months. These results from MagnetisMM-1, coupled with results from MagnetisMM-3 and MagnetisMM-5, provide strong support for further studies and the development of elranatamab for patients with RRMM.

Association of metabolic tumor volume and clinical outcomes in the ZUMA-7 trial of axi-cel for large B cell lymphoma

259. Association of Metabolic Tumor Volume (MTV) and Clinical Outcomes in Second-Line (2L) Relapsed/Refractory (R/R) Large B-Cell Lymphoma (LBCL) Following Axicabtagene Ciloleucel (Axi-Cel) Versus Standard-of-Care (SOC) Therapy in ZUMA-7

Frederick L. Locke (Moffitt Cancer Center, Tampa, United States) presented a study investigating the association of metabolic tumor volume (MTV) with baseline characteristics and clinical outcomes for patients enrolled on ZUMA-7, a phase-3 trial that demonstrated the superiority of axicabtagene ciloleucel (axi-cel) to standard of care for patients with relapsed or refractory large B cell lymphoma (RR-LBCL) in the second line. MTV was obtained from attenuation-corrected whole-body FDG PET scans performed at screening using a predefined, semiautomated approach. Median MTV was 230.24 mL, which was similar across treatment arms. MTV correlated positively with tumor diameter (sum of product diameters; SPD) and with lactate dehydrogenase (LDH). Event-free survival (EFS) and progression-free survival (PFS) with axi-cel were superior to SOC for patients with both low and high MTV. In both treatment arms, PFS was shorter in patients with high compared to low MTV. MTV was lower in patients with an ongoing response to axi-cel and in patients achieving a complete response with axi-cel. Median MTV was also higher in patients receiving axi-cel who experienced neurological events or cytokine release syndrome (CRS) >= Grade 3. This is the first analysis to examine MTV in a large, randomized study of patients with RR-LBCL, and data are similar to previous studies with SPD and LDH-based subgroups showing axi-cel produces superior clinical outcomes in patients with high MTV and with low MTV. Tumor burden per SPD did not impact efficacy of axi-cel, but low MTV was associated with improved outcomes with axi-cel, suggesting MTV may be a more accurate measure of tumor burden than sum of product diameters (SPD).

Changes in the native immune cell population associated with durable response to CAR T cell therapy

261. Durable Response to CD19 CAR T Cell Therapy Is Associated with Cytotoxicity and Clonotypic Expansion of the Native T Cell Repertoire

Giulia Cheloni (Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States) reported on a study to identify CAR T-cell induced epitope spreading as a mechanism underlying durable responses to axicabtagene ciloleucel (axi-cel) for patients enrolled on the ZUMA-1, a phase 1 trial of axi-cel in relapsed or refractory large B-cell lymphoma (RR-LBCL). In the primary analysis of the ZUMA-1 trial, axi-cel achieved durable remissions in a subset of patients with RR-LBCL in the absence of CAR T cells persistence. CAR T-cell expansion was not associated with durable response. To test the hypothesis that CAR T-induced epitope spreading can activate T-cell immunity, the authors analyzed single-cell transcriptomic analyses of peripheral blood samples from patients enrolled on ZUMA-1. Samples were collected from 32 patients, of which 29 had available corresponding clinical data. Patients represented non-responders (n=8), patients who relapsed within one year of CAR T infusion (n=9), and long-term responders (n=12). Circulating CAR T cells were minimally detected at all timepoints in all patient populations. Long-term responders exhibited a high proportion of native T cells compared to other cohorts and a higher CD8/CD4 T cell ratio. Native CD8 T cells from long-term responders exhibited a cytotoxic gene signature. Long-term responders also showed a higher proportion of distinct T cell subtypes, including cytotoxic CD8 T cells and T cells expressing NK markers or memory markers as well as a higher abundance of cytotoxic CD4 lymphocytes. Lower levels of regulatory T cells (Treg) were observed in long term responders, whereas patients who relapsed exhibited increased expansion of Treg. Long term responders also exhibited lower proportions of monocytes and NK cells and higher clonal expansion associated with cytotoxicity. TCR sequence similarity among different responders indicated that axi-cel triggers a T cell response against common antigens. Long term response to axi-cel for RR-LBCL is associated with clonotypic expansion of the native cell CD8 T-cell repertoire, and this study provides promise in identifying factors that could predict patient response and in furthering the understanding of immunogenic mechanisms behind durable responses to CAR T cell therapy.

Preliminary safety and efficacy data for GPRC5D-targeted CAR T therapy for multiple myeloma

364. Clinical Activity of BMS-986393 (CC-95266), a G Protein–Coupled Receptor Class C Group 5 Member D (GPRC5D)–Targeted Chimeric Antigen Receptor (CAR) T Cell Therapy, in Patients with Relapsed and/or Refractory (R/R) Multiple Myeloma (MM): First Results from a Phase 1, Multicenter, Open-Label Study

Jesus Berdeja (Sarah Cannon Research Institute, Nashville, United States) presented preliminary results from CC-95266-MM-001, a Phase 1 multicenter study evaluating BMS-986393 (CC-95266), humanized GPRC5D-targeting autologous CAR T cell therapy in patients with relapsed or refractory Multiple Myeloma (RRMM). GPCRC5D, an orphan receptor expressed on MM cells, has shown success in previous studies as a potential therapeutic target for MM. Of the 33 patients enrolled in the study, 18 (54.5%) had received prior BCMA therapy. 13 of those patients had been treated with BCMA-directed CAR T cells. 72.7% of patients experienced grade 3 or 4 treatment-related adverse events, and two patients experienced dose-limiting toxicities. Cytokine release syndrome was observed in 63.6% of patients, 6.1% at Grade 3-4. All on-target, off-tumor adverse events (dysgeusia and nail changes) were Grade 1 with most (78.6%) not requiring intervention. No cerebellar toxicities or high-grade ICANS were observed. Overall response rate (ORR) at all dose levels was 89.5% with 47.4% achieving a complete response or better. Of the patients who had not received prior BCMA therapy, ORR was 100%; for patients who had received prior BCMA therapy, ORR was 77.8%. 15 of 17 patients with a partial response or better had an ongoing response. All evaluable patients with a complete response were minimum residual disease-negative at 3 months after treatment. Dose expansion studies are underway to define the recommended phase 2 dose. These preliminary efficacy and safety data are promising, indicating GPRC5D-directed CAR T cell therapy may be a new treatment option for patients with RRMM.

Second-generation CAR T cells for newly diagnosed high-risk multiple myeloma

366. Phase I Open-Label Single-Arm Study of BCMA/CD19 Dual-Targeting FasTCAR-T Cells (GC012F) As First-Line Therapy for Transplant-Eligible Newly Diagnosed High-Risk Multiple Myeloma

Juan Du (Shanghai Changzheng Hospital, Shanghai, China) reported preliminary results from a phase 1 single-arm, open-label, first-in-human trial of GC012F, an autologous second-generation BCMA and CD19 dual-targeting CAR T cell, in the first line treatment of high-risk newly diagnosed multiple myeloma (HR-NDMM). BCMA is universally expressed on malignant multiple myeloma, while CD19 is expressed on a minor myeloma-propogating tumor population. GC012F was manufactured using the FasTCAR-T next-day platform allowing for rapid CAR-T production (22-36 hours). At the time or reporting, 16 patients with HR-NDMM (ISS 2-3, high risk cytogenetics, extramedullary plasmacytoma) were enrolled at three dose levels (1, 2, and 3 x 10⁶ cells/kg) with a median follow up 5.3 months. 25% (4/16) of patients experienced cytokine release syndrome, and all cases were grade 1 or 2. No ICANS or neurotoxicity was observed. Cytopenias, including high grade (>= 3), were common. The overall response rate (ORR) was 100%, with all patients achieving minimal residual disease (MRD) negativity. 100% ongoing MRD-negativity was observed for the-evaluable patients at 6 months (n=8) and 12 months (n=3). 88% of patient achieved MRD negativity and a stringent complete response. CAR T cell expansion was observed in all patients at 10 days post-infusion with persistence past 100 days for some patients. Although these results need to be validated with further assessment of GC012F with more patients and longer follow-up, GC012F has a favorable safety profile and produces encouraging anti-tumor activity in transplant eligible patients with HR-NDMM. This investigation also supports the the clinical efficacy of novel accelerated cellular therapy manufacturing platforms such as FasTCAR-T.

CAR-T cell infusion activates cytotoxic bystander T cells

482. CAR-T Cell Infusion Results in Activation of CD160+/NKG2D+/CCL5+ Non-CAR CD8+ Cytotoxic ‘Bystander’ T Cells in Both Non-Human Primates (NHP) and Patients Receiving B-Cell-Directed CAR-Ts

Ulrike Gerdemann (Boston Children’s Hospital, Harvard Medical School, Boston, United States) presented a study investigating the anti-leukemic activity of bystander CAR-negative T-cells, termed the “bystander effect,” during CAR T-cell infusion. Using a non-human primate (NHP) CD20-targeting CAR-T cell model, the authors observed expansion of an activated CD8+ CAR-negative T-cells (bystander T-cells) population that coincided with peak CAR-T cell expansion, but not in the CD4+ CAR-negative compartment. Single cell RNA sequencing (ScRNA-seq) characterized the CD8+ bystander T cells during peak expansion with an activated cytotoxic signature and upregulation of NK-cell markers (NKG2D, CD94, CD160, CCL5, NKG7). ScRNA-Seq identified a similar phenotype of activated CD8+ CAR-negative cells in 6 patients treated with tisagenlecleucel (tisa-cel) in the PREDICT trial for acute lymphoblastic luekemia. Among an array of cytokine release syndrome related cytokines, IL-2 and IL-15 were found to activate bystander cells in vitro. IL-2 and IL-15 activated T-cells sorted for NKG2D, CD160, and CD94 positivity were found to have leukemia directed killing compared to the negative sorted population. These data are the first demonstration that CAR T cells induce a bystander effect in CD8 CAR-negative T cells in non-human primate model and in human patients receiving tisa-cel treatment. Further studies will provide more insights to how endogenous T cells contribute to anti-cancer effects through CAR-independent mechanisms.

Chimeric antigen receptor costimulatory domains play a role in CAR T cell dysfunction

973. Costimulatory Domains Direct Distinct Fates of CAR T Cell Dysfunction

Nathan Singh (Washington University School of Medicine, Saint Louis, United States) presented a study investigating the relationship between costimulatory domains of chimeric antigen receptors (CAR) to T cell exhaustion. CD28- (19/28) or 41BB-based (19/BB) CD19 CAR T cells underwent chronic CD19-antigen stimulation to recapitulate T-cell dysfunction and were then characterized by transcriptional and genomic profiling. Both CAR T-cell products became dysfunctional about 10 to 12 days after chronic stimulation in vitro. Dysfunctional 19/28 cells exhibited classical T cell exhaustion profiles, expressing high levels of PDCD1, CTLA4, TOX and NR4A. Dysfunctional 19/BB CAR T-cells displayed a unique dysfunctional transcription profile characterized by expression of II MHC genes as and T cell memory (LEF1, TCF7 and IL7R). A similar dysfunctional gene signature was identified in 41BB-based CAR-T cells from a patient with progressive non-Hodgkin lymphoma at 3 months after T cell infusion. To identify the transcriptional program underlying non-classical T-cell transcriptional profile in 19/BB dysfunction, the authors performed single cell profiling and ATAC-sequencing on peripheral blood from a patient with a partial response and later progressive disease after treatment with tisagenlecleucel. Expression of the transcription factor FOXO3 (forkhead box O-3) was reactivated in this patient’s exhausted CAR T-cells consistent with single cell profiling indicated dysfunctional 19/BB cells have increased chromatin accessibility at binding sites for FOXO3. Disruption of FOXO3 locus delayed onset of dysfunction in 19/BB but not 19/28 CAR-T cells in chronic stimulation assays, and overexpression of FOXO3 was associated with early loss of anti-tumor efficacy in 19/BB cells. In a murine xenograft model of acute lymphoblastic leukemia, CAR-T cells knocked out for FOXO3 exhibited increased tumor control. This study indicates that CAR costimulatory domains play a role in CAR T cell dysfunction, and FOXO3 drives dysfunction in 41BB-based CAR. Further study is needed to identify methods to bypass mechanisms of T cell dysfunction, improving efficacy of CAR T cells

A preclinical model of cytokine release syndrome and neutropenia

486. A Novel IL2Rα-/- Model for CAR-T Toxicity in Acute Lymphoblastic Leukemia Recapitulates Cytokine Release Syndrome and Neutropenia

Payal Goala (University of South Florida, Tampa, United States) reported on the development of a single in vivo models to emulate multiple CAR T-cell inflammation related toxicities of cytokine release syndrome (CRS) and neutropenia simultaneously. Prior work has shown that higher grade CRS is associated with higher incidence of neutropenia and that neutropenia is associated with a higher infection rate and poor survival outcomes after CAR T cell therapy. IL-2 receptor alpha (IL-2R alpha) is known to regulate cytokine-mediated inflammation, self tolerance, and T-cell expansion. The authors hypothesized that an in vivo murine knockout model of IL-2R alpha (IL-2R alpha KO) could recapitulate inflammation related adverse events. Infusion of CAR-T cells in non-tumor bearing, non-lymphodepleted IL-2R alpha KO recapitulated a CRS related cytokine profile, including elevated levels of IL-6, TNF alpha, and IFN gamma, and co-occurring neutropenia compared to wild-type mice post-CAR T infusion. Histopathologic examination confirmed presence of CRS related secondary hemophagocytic lymphohistiocytosis in target organs of CAR T-cell treated IL-2R alpha KO. These mice also exhibited decreased neutrophil maturation and proliferation and increased neutrophil apoptosis. Using murine directed IL-6-receptor and IFNγ therapeutic antibodies ameliorated CRS symptoms but not neutropenia in IL-2R alpha KO mice. Further study of this mouse model will provide insights to communication between CAR T cells with other host immune components and identify factors that cause co-occurrence of CRS and neutropenia. 

Primary results from the TRANSFORM study of liso-cel as second-line treatment for large B-cell lymphoma

655. Lisocabtagene Maraleucel (liso-cel) Versus Standard of Care (SOC) with Salvage Chemotherapy Followed By Autologous Stem Cell Transplantation (ASCT) As Second-Line (2L) Treatment in Patients with Relapsed or Refractory Large B-Cell Lymphoma (LBCL): Primary Analysis of the Randomized, Phase 3 Transform Study

Jeremy S. Abramson (Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, United States) presented results from primary analysis of the TRANSFORM study, a global, multicenter phase 3 trial studying safety and efficacy of lisocabtagene maraleucel (liso-cel) versus standard of care (SOC; chemoimmunotherapy followed by high-dose chemotherapy and autologous stem cell transplant) for second-line treatment of patients with refractory or relapsed large B cell lymphoma (RR-LBCL). 184 patients were randomized 1:1 to the liso-cel arm or SOC arm. Crossover from the SOC arm to the liso-cel arm was allowed following treatment failure. At a median follow-up of 17.5 months, median event free survival (EFS) was not reached for liso-cel arm, compared to 2.4 months for SOC arm (HR 0.356), and this improvement was statistically significant. EFS favored liso-cel across all subgroups. Complete response (CR) rate was significantly higher for liso-cel, at 74% vs 43% for standard of care. Median duration of CR (DOCR) was not reached for liso-cel and 9.3 months for SOC (HR 0.483). Median progression free survival for liso-cel was significantly higher than SOC (Not reached vs. 6.2 months, respectively; HR 0.400). Overall survival (OS) favored the liso-cel arm over the SOC arm (NR vs 29.9 months, HR 0.724), but this increase was not statistically significant. At 18 months, 73.1% of patients in the liso-cel arm were alive, compared to 60.6% of patients in the SOC arm. When OS analysis adjusted for crossover of patients from the SOC arm to the liso-cel arm (n=61), the 18-month OS rate for the liso-cel arm was 73.1%, compared to 54.1% for the SOC arm. Within the crossover subgroup who had received liso-cel (n=57), CR rate was 53% and median PFS and EFS was 5.9 mos. These lower efficacy outcomes for crossover patients receiving liso-cel as third-line therapy suggest earlier treatment with liso-cel carries more survival benefits. Safety results consistent with results from interim analysis, with 49% of patients experienced cytokine release syndrome (CRS), and only 1 case of Grade 3 CRS was reported. These data reinforce the use of liso-cel as an effective second-line treatment for patients with primary r/r LBCL.

Real-world outcomes of tisagenlecleucel for B-cell non-Hodgkin's lymphoma

656. Real-World Outcomes for Patients with Relapsed or Refractory (R/R) Aggressive B-Cell Non-Hodgkin's Lymphoma (aBNHL) Treated with Commercial Tisagenlecleucel: Subgroup Analyses from the Center for International Blood and Marrow Transplant Research (CIBMTR) Registry

Daniel J. Landsburg (University of Pennsylvania, Philadelphia, United States) presented a non-interventional prospective study analyzing the efficacy and safety of commercial tisagenlecleucel (tisa-cel) for relapsed or refractory (RR) aggressive B-Cell non-Hodgkin's lymphoma (aBNHL) based on a large real world cohort from the Center for International Blood and Marrow Transplant Research (CIBMTR) Registry study. Data from the CIBMTR Registry show a similar efficacy and more favorable safety profile compared to the Phase II JULIET trial of tisa-cel for RR-aBNHL, and the CIBMTR registry included a more heterogeneous patient population than those enrolled in the JULIET study. Data were collected from 1159 patients who received commercial tisa-cel, which were then divided into safety and efficacy cohorts for analysis. 44% of patients had a medical comorbidity, and 6.7% of patients had a morphologic complete remission at the time of infusion. Patients were stratified by eligibility for JULIET, LDH level, and lymphodepleting chemotherapy regimen. In the efficacy set (n=968), at the 24-month follow-up, overall response rate (ORR) was 59.5%, and the complete response (CR) rate was 44.5%. Estimated progression free survival rate was 28.4%, estimated rate of ongoing response was 52.6%, and estimated overall survival was 43.6%. Patients who achieved a CR exhibited better progression free survival, duration of response, and overall survival. Patients with comorbidities had similar efficacy outcomes than patients without comorbidities. Morphologic CR at the time of infusion and normal lactate dehydrogenase level (LDH) were associated with improved efficacy outcomes. The type of lymphodepletion chemotherapy did not affect clinical outcomes. In the safety cohort (n=990), 58.2% of patients experienced cytokine release syndrome (CRS), and CRS >= Grade 3 was observed in 6.0% of patients. The presence of comorbidities had no association with safety outcomes. Patients in morphologic CR at the time of infusion has lower rates of CRS and ICANS. Patients with ECOG performance status >= 2 had increased rates of ICANS and high grade CRS. These data from the largest real-world cohort of patients treated with tisa-cel indicate durable efficacy and a favorable long-term safety profile. Subgroup analyses indicate that tisa-cel can be used to treat a broad patient population of patients with aBNHL.

Updated efficacy and safety data for Mosunetuzumab, a bispecific monoclonal antibody for follicular lymphoma

610. Mosunetuzumab Monotherapy Demonstrates Durable Efficacy with a Manageable Safety Profile in Patients with Relapsed/Refractory Follicular Lymphoma Who Received ≥2 Prior Therapies: Updated Results from a Pivotal Phase II Study

Nancy L. Bartlett (Washington University School of Medicine, St Louis, United States) presented updated results from a Phase II study of Mosunetuzumab (Mosun), a first-in-class CD20 x CD3 T cell engaging bispecific monoclonal antibody, for patients with relapsed/refractory follicular lymphoma (RR-FL) who had received >= 2 prior therapies. 90 patients enrolled in study; 77% of patients had stage III/IV disease, and 53% of patients were double refractory to a last prior chemoimmunotherapy line. Treatment was performed on an outpatient basis. At a median follow-up of 28.3 months, overall response rate (ORR) was 77.8 %, and complete response (CR) rate was 60.0%. Median duration of response (DOR) and duration of CR have not been reached, and the 24-month rate of duration of CR was 63%. Mosun exhibited higher clinical efficacy compared to patients’ last prior therapy. The CR rate of last prior therapy was 35.6%, compared to 60.0% for Mosun, and median 24-month progression-free survival for last prior therapy was 23.5%, compared to 51.4% for Mosun. No new cytokine release syndrome (CRS) events or adverse events >= Grade 3 were reported since the initial report. 44% of all patients experienced any grade of CRS, with 1% experiencing Grade 3 and 1% experiencing Grade 4 CRS. These updated results indicate that durable anti-tumor responses to Mosun continue to be observed, and Mosun is associated with better clinical outcomes than patients’ prior therapies. The safety profile supports continuing to administer Mosun on an outpatient basis.

Efficacy and safety of Glofitamab, a CD20 X CD3 bispecific T cell engager for first line treatment of diffuse large B-cell lymphoma

737. Glofitamab Plus R-CHOP Induces High Response Rates and a Favorable Safety Profile in Patients with Previously Untreated Diffuse Large B-Cell Lymphoma (DLBCL): Results from a Phase Ib Study

Max S. Topp (Universitätsklinikum Würzburg, Würzburg, Germany) presented results from NP40126, a Phase 1b study Glofitamab (Glofit) in combination with R-CHOP as first-line therapy for patients with diffuse large B-cell lymphoma (DLBCL). Glofitamab is a CD20 x CD3 T cell engaging bispecific monoclonal antibody with a 2:1 configuration (CD20:CD3) to confer high-avidity bivalent binding to CD20 on B cells. 56 patients were enrolled with a median age of 68. 55 patients were evaluable for end of treatment reporting. 53 patients received standard 21-day R-CHOP with Glofit that was added during the second cycle(C) in step-up dosing format (C2 Day [D]8, 2.5mg; C2D15, 10mg) to a target dose of 30mg on C3D8. At a median follow-up of 5.6 months, the complete metabolic response rate was 75.5% (40/53), and overall response rate was 86.8% (46/53). Almost all patients experienced a reduction in tumor volume, and a high response rate was observed across all IPI subgroups. In the safety population (n=56), 64.3% of patients (36/56) experienced adverse events (AEs) >= Grade 3, and 23.2% (13/56) were related to Glofit. 1 patient discontinued treatment due to Glofit-related AEs, and 12 patients experienced dose modifications or interruption of Glofit therapy. One patient died prior to receiving Glofit due to a grade 5 rituximab infusion reaction. Cytokine release syndrome were observed in 10.7% of patients (6/56), and no CRS events were >= Grade 3. Two patients received tocilizumab for CRS. Most CRS events occurred during the first exposure and during step-up dosing (C2D8 and C2D15). No immune effector cell-associated neurotoxicity syndrome (ICANS) events were encountered. Three patients died from COVID. The requirement for hospitalization was removed following the safety run-in, so 42 patients in NP40126 were treated without mandatory hospitalization. A Glofit + Poli-R-CHP cohort is ongoing. The efficacy and safety data provide promise that Glofit can be combined with R-CHOP for first-line treatment of DLBCL in an outpatient setting. A cohort of Glofit + Pola-R-CHP is ongoing.

An off-the shelf 2:1 GPRC5D-T cell bispecific antibody for multiple myeloma

863. RG6234: A Novel 2:1 GPRC5D T Cell Bispecific Antibody Exhibits Best in Class Potential for the Treatment of Multiple Myeloma As a Monotherapy and in Combination

Jan Eckmann (Roche Diagnostics GmbH, Penzberg, Germany) reported preclinical evaluation of efficacy and dosing of Forimtamig (RG6234), an off-the shelf 2:1 GPRC5D-T cell bispecific antibody, in murine models of multiple myeloma (MM). Forimtamig is designed with a 2:1 head to tail geometry that allows for high avidity binding to myeloma. A silenced fc domain extends the products half-life and reduces infusion racitons. Anti-tumor activity of Forimtamig was compared to a 1:1 GPRC5D-TCB (Talquetamab) and a 2:1 BCMA-TCB in a xenograft murine MM model humanized with engrafted lymphocytes (HuNSG). Forimtamig was superior to the other tested TCB formats, eradicating tumors in mice at all tested doses despite the lower GPRC5D expression levels compared to BCMA. Forimtamig induced activation of tumor infiltrating lymphocytes and killed MM cells in ex vivo functional assays using bone marrow (BM) aspirates from patients (n=10) with MM, achieving higher T-cell CD25 upregulation and EC50 at lower concentrations compared to other TCBs. Combining Forimtamig with standard of care therapeutics daratumumab and/or pomalidomide boosted anti-tumor activity an autologous BM aspirates from MM patients by 40 to 80% without compromising T-cell viability. The HuNSG mice with engrafted MM cell lines was used for longitudinal analysis of anti tumor activity and blood biomarker assessment. Forimtamig in combination with daratumumab or lenalidomide exhibited anti-tumor activity in the bone marrow of humanized mice. The authors characterized circulating T cell margination, marrow T cell proliferation, and T cell effector memory differentiation in HuNSG mice treated with Forimtamig. Peak cytokine release consistent with cytokine-release syndrome were also observed. A step-up dosing strategy of Forimtamig in the HuNSG model did not significantly affect anti-tumor activity, but significantly ameliorated peak-cytokine levels. Forimtamig was found to have superior potency and efficacy compared to other TCBs in preclinical model, and its anti-tumor activity is enhanced in combination with other SOC therapies for MM. Phase 1 dose escalation trials have confirmed these preclinical studies, and optimization of subcutaneous dosing is ongoing in preparation for trials of dose expansion and combination therapy with the current standard of care.

Second-generation CD123-CAR T cell therapy for acute myeloid leukemia 

981. Ameli-01: A Phase I Trial of UCART123v1.2, an Anti-CD123 Allogeneic CAR-T Cell Product, in Adult Patients with Relapsed or Refractory (R/R) CD123+ Acute Myeloid Leukemia (AML)

David A. Sallman (Moffitt Cancer Center, Tampa, United States) presented results from AMELI-01, a Phase 1, open-label, dose-escalation trial for UCART123v1.2 (UCART), a genetically modified allogeneic anti-CD123 T-cell product manufactured from non-HLA-matched healthy donor cells, for relapsed or refractory CD123-positive acute myeloid leukemia (AML). TALEN® disruption of TRAC and CD52 in UCART123v1.2 reduces the risk of graft versus host disease and allows for alemtuzumab (CD52-directed) lymphodepletion, respectively. 18 patients were enrolled in the study, and 17 patients received UCART after lymphodepletion. Two methods of lymphodepletion (LD) were investigated: lymphodepletion was performed with fludarabine and cyclophosphamide (FC) for 8 patients and with FC + alemtuzumab (FCA) for 9 patients. Cytokine release syndrome was observed in all patients who received UCART, with 4 cases >= Grade 3 (2 in the FC arm; 2 in the FCA arm) one of which was Grade 5 (FCA arm). Neurotoxicity was relatively rare, with ICANS observed in 2/17 patients, and the one case of ICANS >= Grade 3 occurred in the FC arm. Anti-cancer activity was observed in 4 patients, all who received dose level 2 (DL2; 6.25 x 10⁵ cells/kg) or higher. Of the 2 responders in the FC arm, one patient achieved stable disease, and one patient achieved a morphological leukemia-free state. In the FCA arm, one patient achieved stable disease with 90% blast reduction at Day 28 (subsequently received a donor lymphocyte infusion) and one patient achieved an initial minimal residual disease (MRD)-positive complete response (CR) at day 28 that deepened to an MRD-negative CR that was maintained at the 12-month check-in. The FC regimen was inadequate for lymphodepletion with 7 of 8 patients recovering host lymphocytes prior to day 28. In contrast, all patients in the FCA arm exhibited depletion of lymphocytes through day 28, indicating that addition of alemtuzumab to the lymphodepletion protocol prolonged the period of effective host lymphopenia. Furthermore, 3 patients in the FC arm exhibited UCART expansion, compared to 7 (80%) patients in the FCA arm who had 10x more vector copies than the FC arm. The FC arm was closed due to poor expansion. The trial continues to enroll patients on the FCA arm with plans to incorporate a second infusion of UCART123 to provide a second peak of UCART expansion and allow for clearance of disease and sustained anti-leukemic activity. The authors conclude that the addition of alemtuzumab allows for higher levels of lymphodepletion and improved CART expansion in this off the shelf allogeneic CART product.

Pretreatment with tafasitamab reduces severity and incidence of cytokine release syndrome in preclinical models

977. CD19 Antigen Occupancy on Cancer Cells with the CD19 Monoclonal Antibody Tafasitamab Improves the Activation, Antitumor Efficacy, and Safety Profile of CART19 Cell Therapy

Ultrasensitive ctDNA correlates with PET/CT response assessments in patients treated with CD30 CAR-T cell therapy for relapsed or refractory Classical Hodgkin Lymphoma

984 Ultrasensitive Circulating Tumor DNA (ctDNA) Dynamics after Autologous CD30.CAR-T Cell Therapy for Relapsed or Refractory (r/r) Classical Hodgkin Lymphoma (CHARIOT Trial)

David Kurts (Stanford University, Palo Alto, United States) presented an exploratory analysis of ultrasensitive circulating tumor DNA (ctDNA) as a tool to track response and predict progression for patients enrolled in a pilot cohort, single-arm, phase 2 trial (CHARIOT Trial) of autologous CD30.CAR-T cells for the treatment of relapsed and refractory classic Hodgkin Lymphoma (cHL). Here the authors used a novel method of ultrasensitive ctDNA-based mininmal residual disease (MRD) detection by Phased Variant Enrichment & Detection Sequencing (PhasED-Seq), which offers a 100-fold lower level of detection compared to earlier generations of ctDNA. cHL ideal for this type of platform because tumor ctDNA is readily detectable in the blood and tissue mutational sequencing may be difficult due to the paucity of malignant cells within the tissue tumor biopsy. In this initial pilot segment of the study, plasma was collected for ctDNA analysis pre-CD30.CAR-T cell infusion, at day 42, at progression of disease, as well as prior to and following a second infusion (n=6; if product was available). PET/CT evaluation was performed at day 42 and at progression and reviewed by an independent radiologist by Lugano criteria. CtDNA was detected in all patients who had not received bridging therapy (n=12). For the 13 patients with detectable ctDNA, the authors observed that day 42 ctDNA levels correlated significantly with PET Deauville score. Patients achieving a complete response (CR; n=7) as best overall response (BORR) as assessed by day 42 PET/CT had a mean ctDNA log reduction of -3, with four patients having undetectable ctDNA. Patients with progressive disease (PD) as BORR had a minimal reduction or increased in ctDNA compared to patients with stable disease (SD) or partial response (PR). CtDNA level dropped following the second infusion of CD30.CAR-T infusion for those patients for whom a second product was available and necessary (n=6). One patient, who achieved a radiographic CR at day 42 and at month 3 PET/CT but had detectable ctDNA at day 42, went on to have progressive disease at six months. Based on this observation, the authors argue that ctDNA is sensitive enough to detect radiologically occult disease. In summary, this novel method of ctDNA detection is useful for obtaining ultrasensitive liquid tumor biopsies, particularly in situations where tissue sequencing is technically challenging such as cHL. ctDNA is a promising tool for assessing response to CD30.CAR-T cells and clearance of ctDNA may be a marker for durable responses to novel agents.