MTV273 / University of Pennsylvania, Novartis - LARVOL DELTA

PRE-CLINICAL RESULTS OF A HUMANIZED CART-BCMA FOR MULTIPLE MYELOMA PATIENTS (EHA 2018) - P1; "We generated a humanized CART-BCMA that is as efficient as the murine one, but might favor a longer persistence of CART cells in patients. In the next months, this CAR will be translated into the clinic for MM patients. Furthermore, a-MSH potentially could be used as an adjuvant to ameliorate CRS without impacting negatively in the CART activity."

IO biomarker • Multiple Myeloma

Clinical Predictors of T Cell Fitness for CAR T Cell Manufacturing and Efficacy in Multiple Myeloma (ASH 2018) - P1, P1/2, P2; "...In an accompanying abstract (Cohen et al.), we report that higher percentage of early-mem T cells and CD4/CD8 ratio within the leukapheresis product are associated with favorable clinical response to anti-BCMA CAR T cells (CART-BCMA) in relapsed/refractory MM...Results : The post-ind cohort includes 38 patients with median age 55y (range 41-68) and prior exposure to lenalidomide (22), bortezomib (21), dexamethasone (38), cyclophosphamide (8), vincristine (2), thalidomide (8), and doxorubicin (4); median time from first systemic therapy to leukapheresis was 152 days (range 53-1886) with a median of 1 prior line of therapy (range 1-4). The rel/ref cohort included 25 patients with median age 58y (range 44-75), median 7 prior lines of therapy (range 3-13), and previously exposed to lenalidomide (25), bortezomib (25), pomalidomide (23), carfilzomib/oprozomib (24), daratumumab (19), cyclophosphamide (25), autologous SCT (23), allogeneic SCT (1), and anti-PD1...

CAR T-Cell Therapy • Clinical • PD(L)-1 Biomarker • Biosimilar • Chronic Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Indolent Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Oncology

Safety and Efficacy of B-Cell Maturation Antigen (BCMA)-Specific Chimeric Antigen Receptor T Cells (CART-BCMA) with Cyclophosphamide Conditioning for Refractory Multiple Myeloma (MM) (ASH 2017) - "...Median lines of therapy is 7 (range 3-11); 100% are proteasome inhibitor and IMID-refractory, 67% daratumumab-refractory...In Cohorts 2 and 3 (n=12), CRS has occurred in 9 pts (3 grade 3, 0 grade 4, none requiring tocilizumab), and neurotoxicity in 1 pt (grade 2 confusion/aphasia), with no unexpected/dose-limiting toxicities, and no treatment-related deaths... CART-BCMA infusions following Cy lymphodepletion are feasible and have significant clinical activity in highly-refractory MM pts with poor-risk genetics and limited treatment options. Efficacy appears lower at the 107 dose, compared with 108, and remaining pts are now being enrolled in Cohort 3. CRS remains a common but manageable toxicity."

CAR T-Cell Therapy • Biosimilar • Multiple Myeloma • Ophthalmology

B-Cell Maturation Antigen (BCMA)-Specific Chimeric Antigen Receptor T Cells (CART-BCMA) for Multiple Myeloma (MM): Initial Safety and Efficacy from a Phase I Study (ASH 2016) - "This resolved after anti-epileptics, high-dose methylprednisolone and cyclophosphamide, without long-term neurologic sequelae. Cytokine release syndrome (CRS) occurred in 5 patients: 2 grade 3 requiring tocilizumab (pts 01 and 03), 1 grade 2, and 2 grade 1. CART-BCMA cells can be manufactured from heavily-pretreated MM pts, and demonstrate promising in vivo expansion and clinical activity, even without lymphodepleting conditioning. Depth of response correlates with degree of CART-BCMA expansion and CRS. Toxicities to date include CRS and in 1 pt, severe reversible neurotoxicity, as described in other CAR T cell studies."

P1 data • Acute Lymphocytic Leukemia • Biosimilar • Cardiovascular • Epilepsy • Hematological Malignancies • Leukemia • Multiple Myeloma • Oncology • Renal Disease • Venous Thromboembolism

The phase I clinical study of CART targeting BCMA with humanized alpaca-derived single-domain antibody as antigen recognition domain. (ASCO 2019) - P1; "...We developed CART cells (CART-BCMA) using one single-domain antibody as recognition domain... Our result demonstrates the promising efficacy compared with other reported results of CART targeting BCMA, and supports further development of this anti-RRMM cellular immunotherapy. Clinical trial information: NCT03661554"

Clinical • IO Biomarker • P1 data

[VIRTUAL] COMBINED INFUSION OF ANTI-CD19 AND ANTI-BCMA CAR-T CELLS AFTER ASCT IN THE FRONT LINE WAS SUPERIOR TO SINGLE ASCT FOR HIGH RISK MM (EHA 2020) - "Our previous study showed good response for the de novo high risk patients who received CD19 and BCMA-specific CAR-T cell therapy after ASCT in the front line with mild CRS and other side effects (reported on the 2018 ASH meeting)...Study intervention in this clinical trial consisted of 4 cycles of bortezomib-based induction treatment followed stem cell mobilization by cyclophosphamide 3 g/m2...CART-19 (1×107/kg on d0) and CART-BCMA cells as split-dose (40% on d1 and 60% on d2) were infused directly on d14 to d20 after transplantation...The median PFS and OS of the patients in two groups were all not reached but 21-months PFS was 73% and 55% for two groups respectively (p<0.05); 21-months OS was 100% and 61% for each group (p<0.05) (Figure 1). Conclusion Combined infusion of anti-CD19 and anti-BCMA CART cells after ASCT for high risk MM was safe and effective, and can significantly prolong the PFS and OS compared to single ASCT."

CAR T-Cell Therapy • Hematological Malignancies • Multiple Myeloma • Oncology • Transplantation • CD8 • TNFRSF4

Up-front CART-BCMA With or Without huCART19 in High-risk Multiple Myeloma (clinicaltrials.gov) - P1; N=40; Active, not recruiting; Sponsor: University of Pennsylvania; Trial primary completion date: May 2022 ➔ Mar 2036

Clinical • Trial primary completion date • Hematological Malignancies • Multiple Myeloma • Oncology • SOX2

Up-front CART-BCMA With or Without huCART19 in High-risk Multiple Myeloma (clinicaltrials.gov) - P1; N=40; Active, not recruiting; Sponsor: University of Pennsylvania; Trial primary completion date: May 2021 ➔ May 2022

Clinical • Trial primary completion date • Hematological Malignancies • Multiple Myeloma • Oncology • SOX2

B cell maturation antigen-specific CAR T cells are clinically active in multiple myeloma. (PubMed, J Clin Invest) - P1 | "CART-BCMA infusions with or without lymphodepleting chemotherapy are clinically active in heavily-pretreated MM patients."

CAR T-Cell Therapy • Clinical • IO biomarker • Journal • Hematological Disorders • Hematological Malignancies • Multiple Myeloma • Oncology

Up-front CART-BCMA With or Without huCART19 in High-risk Multiple Myeloma (clinicaltrials.gov) - P1; N=40; Active, not recruiting; Sponsor: University of Pennsylvania; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed • Hematological Malignancies • Multiple Myeloma • Oncology

Combination Anti-Bcma and Anti-CD19 CAR T Cells As Consolidation of Response to Prior Therapy in Multiple Myeloma (ASH 2019) - "Both products are dosed at 5x108 CAR+ cells in 3 divided doses (10%, 30%, 60%) after cy 300 mg/m2 + fludarabine 30 mg/m2 daily x 3d (cy/flu). Pts receive maintenance (maint) lenalidomide or pomalidomide beginning d30 or upon recovery from toxicity... Preliminary results support safety and high initial response-rate of CART-BCMA + CTL119 after cy/flu in MM. In pts with low disease burden responding to prior therapy, including first-line therapy, CAR T cells expanded in vivo and generated clinical responses with low-grade CRS and no neurotoxicity. Preliminarily, hematologic toxicity and feasibility of maint seem more favorable in first-line setting."

CAR T-Cell Therapy • IO Biomarker • Cytomegalovirus Infection • Hematological Disorders • Hematological Malignancies • Immunology • Leukemia • Multiple Myeloma • Oncology • Pain • Pancreatitis • Pneumonia • Respiratory Diseases • Septic Shock

"some #ASH20 data 1/x $ALLO UCART-BCMA 57% ORR with FCA precond $CLLS UCART22 n=6 ITT - 1 disc due to LD, n=5 eval 2 CRi / 1 transient blast reduction $LLY LOXO-305 BTKi 60% ORR in MCL/WM/NHL #VelosBio VLS-101 ROR1 ADC ORR 47% MCL & 80% DLBCL" (@BertrandBio)

Diffuse Large B Cell Lymphoma • Oncology • ROR1

[VIRTUAL] Cord-blood derived NK cells, and CAR-T cells, an attractive improved immunotherapy treatment to be considered for hematological malignancies (SITC 2020) - "Administration of autologous T cells modified with a chimeric antigen receptor (CAR) against B cell maturation antigen (BCMA) has achieved high percentages of complete responses. Unfortunately, the lack of persistence of CART-BCMA cells in the patient leads to relapses...Finally, an in vivo model of advanced MM with consecutive challenge to MM cells evidenced that the addition of CB-NK achieved the highest efficacy of the treatment. Conclusions Our results suggest that the addition of ‘off-the-shelf’ CB-NK to CART cells leads to a faster and earlier immune response of CART cells with higher long-term maintenance of the anti-tumor response, suggesting this combinatorial therapy as an attractive immunotherapy option for MM patients."

CAR T-Cell Therapy • IO Biomarker • Hematological Malignancies • Multiple Myeloma • Oncology • IFNG • TNFA

[VIRTUAL] Cord-blood derived NK cells, and CAR-T cells, an attractive improved immunotherapy treatment to be considered for hematological malignancies (SITC 2020) - "Administration of autologous T cells modified with a chimeric antigen receptor (CAR) against B cell maturation antigen (BCMA) has achieved high percentages of complete responses. Unfortunately, the lack of persistence of CART-BCMA cells in the patient leads to relapses...Finally, an in vivo model of advanced MM with consecutive challenge to MM cells evidenced that the addition of CB-NK achieved the highest efficacy of the treatment. Conclusions Our results suggest that the addition of ‘off-the-shelf’ CB-NK to CART cells leads to a faster and earlier immune response of CART cells with higher long-term maintenance of the anti-tumor response, suggesting this combinatorial therapy as an attractive immunotherapy option for MM patients."

CAR T-Cell Therapy • IO Biomarker • Hematological Malignancies • Multiple Myeloma • Oncology • IFNG • TNFA

[VIRTUAL] Is Bridging Radiation (RT) Safe with B Cell Maturation Antigen–targeting Chimeric Antigenic Receptor T Cells (CART-BCMA) Therapy? (ASTRO 2020) - "Materials/ 25 MM subjects were treated in 3 cohorts: 1) 1-5 x 108 CART-BCMA cells (n=9); 2) Cyclophosphamide (Cy) 1.5 g/m2 + 1-5 x 107 CART-BCMA cells (n=5); and 3) Cy 1.5 g/m2 + 1-5 x 108 CART-BCMA cells (n=11). Our results suggest that bridging RT is safe and feasible without worsening rates of severe CRS, neurotoxicity, or hematologic toxicity. Future prospective trials combining RT with CART-BCMA may further optimize safety and long-term efficacy of this novel therapy in relapsed/refractory MM."

Gastrointestinal Disorder • Hematological Malignancies • Multiple Myeloma • Oncology

Up-front CART-BCMA With or Without huCART19 in High-risk Multiple Myeloma (clinicaltrials.gov) - P1; N=39; Recruiting; Sponsor: University of Pennsylvania; Trial completion date: May 2021 ➔ May 2036; Trial primary completion date: May 2020 ➔ May 2021

Clinical • Trial completion date • Trial primary completion date • Hematological Disorders • Hematological Malignancies • Leukemia • Multiple Myeloma • Oncology

CART-BCMA Cells for Multiple Myeloma (clinicaltrials.gov) - P1; N=25; Completed; Sponsor: University of Pennsylvania; Active, not recruiting ➔ Completed

Clinical • Trial completion • Hematological Malignancies • Multiple Myeloma • Oncology

Clinical Trial Using Humanized CART Directed Against BCMA (ARI0002h) in Patients With Relapsed/Refractory Multiple Myeloma to Proteasome Inhibitors, Immunomodulators and Anti-CD38 Antibody. (clinicaltrials.gov) - P1/2; N=36; Recruiting; Sponsor: Sara V. Latorre; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open • IO Biomarker • Hematological Disorders • Hematological Malignancies • Immune Modulation • Inflammation • Multiple Myeloma • Oncology

Clinical Trial Using Humanized CART Directed Against BCMA (ARI0002h) in Patients With Relapsed/Refractory Multiple Myeloma to Proteasome Inhibitors, Immunomodulators and Anti-CD38 Antibody. (clinicaltrials.gov) - P1/2; N=36; Not yet recruiting; Sponsor: Sara V. Latorre

Clinical • IO Biomarker • New P1/2 trial

"👉🏻Dr. Riddell ⁦@fredhutch⁩ #CART BCMA+ gamma secretase inhibitor ⬇️⬇️relapse. Great work🙌🏻 #TCTM20 #TCT2020" (@MDonatoBMT)

Sequential CD19- and Bcma-Specific Chimeric Antigen Receptor T Cell Treatment for RRMM: Report from a Single Center Study (ASH 2019) - "After one month from CARTs infusion, some pts were adminstrated IMiDs for maintence therapy after hematopoietic recovery, including oral thalidomide 50mg/d or lenalidomide 10mg/d. Combined sequential administration of CART-19 and CART-BCMA cells can be manufactured from heavily-treated MM pts, and could elicit sustained remission for RRMM pts. Toxicities can be well tolerated. CARTs early expansion and persistence in vivo post infusion may be predictive of clinical outcome."

CAR T-Cell Therapy • Clinical • IFNG • IL10 • IL6

Combined Infusion of Anti-CD19 and Anti-Bcma CART Cells after Early or Later Transplantation in the Front Line Was Superior to Salvage Therapy for High Risk MM (ASH 2019) - "BuCy or Melphalan were used as conditioning, followed by infusion of autologous stem cells. CART-19 (1×107/kg on d0) and CART-BCMA cells as split-dose (40% on d1 and 60% on d2) were infused directly on d14 to d20 after transplantation...Tocilizumab was used to treating only one patient with grade 3 CRS... Combined infusion of anti-CD19 and anti-BCMA CART cells after ASCT for high risk MM was safe and effective, especially as conjunction therapy to early or later transplant at front line even with primary resistant disease or early disease progress. For those RRMM patients, CART cell therapy followed by ASCT seems to be better to prolong patients’ PFS than CART treatment alone with FC chemotherapy reported in our another study (NCT 03196414)."

CAR T-Cell Therapy • CD8 • IFNG • IL10 • IL17A • IL2 • IL4 • IL6

Allogeneic CAR-T for treatment of relapsed and/or refractory multiple myeloma: four cases report and literatures review (PubMed, Zhonghua Xue Ye Xue Za Zhi) - "They were infused into CART-19 (1×10(7)/kg on day 0) and (4.0-6.8) ×10(7)/kg CART-BCMA cells as split-dose infusions (40% on day 1 and 60% on day 2)...There were early clinical transient events after transfusion. Low amplification and short duration of CAR-T cells in vivo may be the main factors affecting the efficacy."

Clinical • Journal

TANDOM AUTOLOGOUS TRANSPLANTATION AND COMBINED INFUSION OF CD19 AND BCMA-SPECIFIC CHIMERIC ANTIGEN RECEPTOR T CELLS FOR HIGH RISK MM (EBMT 2019) - "Tandom autologous transplantation and combined infusion of CART-19 and CART-BCMA cells could be another choice of consolidation treatment for high risk MM patients. Toxicities to date including CRS and organ function impairment seemed to be mild and reversable. CD19 CAR-T and BCMA CAR-T cells appeared simultaneously in patients' blood after combined infusion even in MRD state."

CAR T-Cell Therapy

Clinical Predictors of T Cell Fitness for CAR T Cell Manufacturing and Efficacy in Multiple Myeloma Using RShiny, FlowType, Citrus and Spade (TRICON 2019) - "Nat Med 2018); T cell fitness is therefore a major determinant of response to CAR T cell therapy. Here, we report that higher frequency of early-mem T cells and CD4/CD8 ratio in the leukapheresis product are associated with favorable clinical response to anti-BCMA CAR T cells (CART-BCMA) in relapsed/refractory MM patients."

CAR T-Cell Therapy • Clinical