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European Hematology Association (EHA)

Novartis’ BCMA-targeted chimeric antigen receptor (CAR) T-cell therapy PHE885 has shown efficacy in relapsed/refractory 

 (R/R MM).
Positive findings from a phase 1 study (NCT04318327) were presented at the European Hematology Association (EHA) 2022 Congress, June 9-12, held both virtually and in Vienna, Austria, by Adam S. Sperling, MD, PhD, Harvard Medical School and Dana-Farber Cancer Institute.

“BCMA-directed CAR T-cell therapies are approved for the treatment of R/R MM. However, prolonged product manufacturing times and a need for longer duration of response are major obstacles in this population, necessitating fast manufacture of a reliable and highly efficacious CAR T-cell product,” Sperling and colleagues wrote.

Out of 27 enrolled patients, 25 (93%) have successfully received PHE885 as of the data cutoff of April 20, 2022. These participants were dosed with 2.5x106 (n = 4; 16%), 5x10

Investigators observed dose-limiting toxicities in 3 participants, these were asymptomatic grade 3 transaminitis at the highest dose level, asymptomatic grade 3 elevated pancreatic enzymes at the second dose level, and grade 4 neutropenia at the first dose level. All patients had at least 1 treatment-related adverse events (AEs) and experienced cytokine release syndrome (CRS). Two patients had grade 3 or higher CRS.

Dual-Targeted CAR T-Cell Therapy Continues to Show Efficacy in R/R Multiple Myeloma



All but 1 patient achieved a clinical response for a 93% objective response rate. Over half of patients (n = 15; 63%) had ongoing responses with a median follow-up of 6.4 months (1.1-15.5 months). There were 6 complete responses and 9 partial responses. Four patients died due to progressive disease.

“This phase 1 study is ongoing, and additional dose levels are being explored to identify an optimal recommended dose for expansion. PGHE994 expands rapidly in vivo, persists for prolonged periods, and demonstrates a stem cell memory phenotype,” Sperling and colleagues concluded.

PHE885 is developed with the use of Novartis' T-Charge platform that retains the naive/Tscm immunophenotype of the input leukapheresis, which could provide high rates of durable responses. The platform is also designed to reduce the manufacturing process time to less than 2 days, which could reduce the need for bridging therapy.

Also presented at the EHA 2022 Congress was an overview of the currently recruiting phase 2 trial (NCT05172596) assessing PHE885, which opened in February 2022. PHE885 will be infused either in the outpatient or inpatient in a single dose of 4×10

 CAR T-cells. Patietns will be monitored for 24 months after infusion. Patients will then be followed up long term for up to 15 years.

The study is primarily assessing best overall response using International Myeloma Working Group criteria. Secondary endpoints include complete response rate, duration of response, progression-free survival, overall survival, rate and durability of minimal residual disease negativity, as well as safety and pharmacokinetics. Exploratory endpoints include assessment of CRS symptoms.


REFERENCES
1. Sperling AS, Nikiforow S, Derman B, et al. Phase I study data update of PHE885, a fully human BCMA-directed CAR-T cell therapy manufactured using the T-charge platform for patients with relapsed/refractory (R/R) multiple myeloma (MM). Presented at: EHA 2022 Congress, June 9-12, Vienna, Austria and virtually. Abstract #P1446
2. Munshi N, Spencer A, Raab MS, et al. Trial-in-progress: Phase II study of PHE885, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy, in adults with relapsed and/or refractory multiple myeloma. Presented at: EHA 2022 Congress, June 9-12, Vienna, Austria and virtually. Abstract #PB1983

The therapy is now being evaluated in a phase 2 study.


T-Charge CAR T-Cell Therapy Shows Efficacy in Multiple Myeloma

CTX130, a first-in-class CD70-targeting allogeneic CAR-T therapy, was shown to have an acceptable safety profile and to produce clinically meaningful responses in patients with heavily pretreated relapsed/refractory (r/r) T-cell lymphoma (TCL), according to findings from COBALT-LYM (NCT04502446), an ongoing global, multicenter, phase 1 clinical trial.

2022 European Hematology Association Annual Meeting

, June 9-17, 2022, in Vienna, Austria and virtual.

Among the 18 patients who had received 1 of 4 dose levels (DL) of CTX130 (DL1, 3x10

) with at least 28 days of follow-up, there were no cases of graft versus host disease nor any instances of tumor lysis syndrome, and no dose-limiting toxicities.

In terms of clinical responses, a higher percentage of patients responded at higher dose levels, with the overall response rate in DL3 and higher (n=10) being 70%, with 30% of these patients achieving complete remission and 40% achieving a partial response. Furthermore, 90% of patients who received DL3 or higher experienced some clinical benefit, which the investigators defined as stable disease or better response.

Based on these results, the investigators concluded that CTX130 has an acceptable safety profile in patients with heavily pretreated r/r TCL and has the potential to provide clinically meaningful benefit.

"We are very pleased with the preliminary results from our COBALT-LYM trial, which showed efficacy and safety that suggest that CTX130, the first allogeneic CAR-T directed against the novel target CD70, can produce deep responses in patients with relapsed or refractory T cell lymphomas," said Samarth Kulkarni, PhD, chief executive officer, 

 "Additionally, we may be able to further optimize the profile by continuing our consolidation dosing strategy. These data reinforce our belief that engineered cell therapies are the future in our fight against cancer and we are well-positioned to be leaders in this field."

As of December 2021, the ages of the patients enrolled in the study ranged from 39 to 78 (median, 67). All patients had been heavily pretreated with systematic therapies (median, 4) and all patients were refractory to their most recent line of therapy. The study included 8 patients with peripheral TCL and 10 patients with cutaneous TCL. Patients who had previously been treated with any CD70-targeting agents were excluded from participation in the study.

Adverse events included infections, cytokine release syndrome (CRS), and immune effector cell-associated neurotoxicity syndrome (ICANS). However, all cases of CRS and ICANS were grades 1 or 2 and either required no specific intervention or resolved following standard CRS management, and neither the frequency nor severity of CRS increased in patients after being redosed with CTX130. Of note, 1 death occurred but was deemed unrelated to the study drug, and there were no treatment-related deaths during the trial.

"While overall survival in a subset of patients with T cell lymphoma has improved with front-line combination chemotherapy, relapsed or refractory patients continue to have very limited treatment options," said Swaminathan P. Iyer, MD, professor, lead of the T Cell Lymphoma Program, Department of Lymphoma/Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, in a statement.

 "The data from the CTX130 trial demonstrate the potential of cell therapies as a new treatment modality for these patients. I am particularly encouraged by the response rates and safety data, which suggest that treatment with CTX130 could elicit clinically meaningful responses, including complete responses, in patients with difficult-to-treat T cell lymphomas."

In addition to the COBALT-LYM study, CTX130 is also being investigated for the treatment of r/r renal cell carcinoma in a phase1 clinical trial called COBALT-RCC (NCT04438083).

1. Iyer SP, Sica RA, Ho PJ, et al. The COBALT-LYM study of CTX130: a phase 1 dose escalation study of CD70-targeted allogeneic CRISPR-Cas9–engineered CAR T cells in patients with relapsed/refractory (r/r) T-cell malignancies. Presented at: 2022 Hybrid Congress of the European Hematology Association (EHA). June 9-12, 2022; Vienna, Austria. Abstract #S262

2. CRISPR Therapeutics presents positiveresults from its phase 1 COBALT-LYM trial of CTX130 in relapsed or refractory T cell malignancies at the 2022 European Hematology Association (EHA) Congress. News release. CRISPR Therapeutics. June 12, 2022. https://firstwordpharma.com/story/5593297

CTX130 is also being investigated for the treatment of r/r renal cell carcinoma in a phase 1 clinical trial called COBALT-RCC (NCT04438083).

CTX130 Shows Acceptable Safety Profile, Clinically Meaningful Responses in R/R T-Cell Lymphoma 

Mustang Bio’s CD20-targeted chimeric antigen receptor (CAR) T-cell therapy MB-106 has shown efficacy in the 

Findings from the trial were presented at the 

European Hematology Association (EHA) 2022 Congress, June 9-12,

 held both virtually and in Vienna, Austria, byMayzar Shadman, MD, MPH, associate professor, clinical research division, Fred Hutchinson Cancer Center, where the trial was conducted.

“We continue to observe a favorable safety profile and high rate of complete response with MB-106 as exhibited by this follicular lymphoma cohort and within a wide range of other hematologic malignancies including CLL, diffuse large B-cell lymphoma (DLBCL) and Waldenstrom macroglobulinemia (WM),” Shadman said in a statement.

“Based on the ongoing progress, MB-106 may be a suitable outpatient treatment for these patients and another immunotherapy option for patients for whom CD19-directed CAR T cell therapy is not effective. Enrollment in this study remains open to patients with CD20+ B-NHLs and CLL, including patients with prior CAR T treatment.”

Anbal-Cel Shows Promising Responses in Large B-Cell Lymphoma

Eighteen patients with FL have been infused with 1x10

 All patients, except for the firstof each dose cohort which were kept for overnight observation, were infused in the outpatient setting. Overall response rate (ORR) was 94% (n = 17) and complete response (CR) rate was 78% (n = 14). Three patients (17%) had a partial response and 1 (5%) experienced disease progression.

One patient experienced pseudo-progression followed by a spontaneous, continuing CR. Another patient had prior CD19 CAR T therapy failure and has also had a continuing CR. Patients with other B-cell non-Hodgkin lymphomas (B-NHLs) including DLBCL and WM had a 100% ORR.

Five patients experienced cytokine release syndrome (CRS), 4 had grade 1 and 1 had grade 2 CRS. No patients with FL experienced immune effector cell associated neurotoxicity syndrome. CAR T-cell expansion was fastest at the highest dose levels although persistence was comparable by day 28.

An additional multicenter trial (NCT05360238) has also opened enrollment to assess MB-106 for relapsed or refractory B-cell non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL) under Mustang Bio’s investigational new drug application.

“Given the ongoing positive progress presented by Dr. Shadman, we look forward to evaluating MB-106 to treat relapsed or refractory B-NHL and CLL in the multicenter clinical trial under Mustang’s IND which is now open to enrollment. MB-106 continues to demonstrate its potential as a safe, effective CAR T therapy that can address the unmet needs of a range of patients with relapsed or refractory B-NHLs, including WM and DLBCL, with outpatient administration,” Manuel Litchman, MD, president and chief executive officer, Mustang Bio, added to the statement.

“It is especially gratifying to see that the DLBCL patient previously reported as a PR has now improved to a CR, which therefore represents a second CR in DLBCL and a second CR in a patient previously treated with CD19-targeted CAR T therapy.”

1. Shadman M, Yeung C, Redman M, et al. Efficacy and safety of a third generation CD20 CART (MB-106) for treatment of relapsed/refractory follicular lymphoma (FL). Presented at: EHA 2022 Congress, June 9-12, Vienna, Austria and virtually. Abstract #S207.
2. Mustang Bio announces updated interim results from Follicular Lymphoma cohort of ongoing phase 1/2 clinical trial of MB-106, CD20-targeted CAR T therapy. News release. Mustang Bio. June 13, 2022. https://www.globenewswire.com/news-release/2022/06/13/2461188/0/en/Mustang-Bio-Announces-Updated-Interim-Results-from-Follicular-Lymphoma-Cohort-of-Ongoing-Phase-1-2-Clinical-Trial-of-MB-106-CD20-Targeted-CAR-T-Therapy.html

Mustang Bio presented data on MB-106 at the 2022 EHA Congress. 

CAR T-Cell Therapy Yields High Response Rates in Follicular Lymphoma 

A 5-plus year follow-up study has demonstrated durable efficacy of tisagenlecleucel (tisa-cel; Kymriah, Novartis) in pediatric and young adult patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL), with 55% of patients still alive after more than 5 years post-treatment and 42% achieving 5-year event-free survival (95%CI, 29-54), according to findings from ELIANA, a phase 2 global multicenter study (NCT02435849) presented at the 

Of the 79 patients who received tisa-cel, 82% achieved complete remission or complete remission with incomplete hematologic recovery within 3 months post-infusion (95% CI, 72-90). The 5-year relapse-free survival rate for these patients was 44% (95% CI, 31-56) and median relapse-free survival was 43 months. Based on these results, the researchers concluded that tisa-cel could be a potentially curative treatment option for patients with r/r B-ALL.

“These data mark a moment of profound hope for children, young adults and their families with relapsed or refractory B-cell ALL, as relapse after five years is rare,” according to Stephan Grupp, MD, PhD, section chief of the Cellular Therapy and Transplant Section, and inaugural director of the Susan S. and Stephen P. Kelly Center for Cancer Immunotherapy at Children's Hospital of Philadelphia (CHOP), said in a statement.

 “Since the approval of Kymriah nearly five years ago, we have been able to offer a truly game-changing option to patients who previously faced a five-year survival rate of less than 10 percent.”

The ages of patients involved in the study ranged from 3 to 24 years (median, 11). All patients had been pretreated with 1 to 8 prior lines of therapy (median, 3), and 61% of the patients had a history of prior stem cell transplant. The 5-year overall survival rate among all study participants was 55% (95% CI, 43-66). Notably, there was no significant difference observed in any efficacy end point between participants age 18 or older who received tisa-cel versus those younger than 18. The researchers noted that 82% of the patients received IVIG at some point post-infusion.

Commonly reported adverse events occurring more than 1 year post-infusion included infection (20%) and cytopenias (6%). Investigators noted that 14% of patients experienced cytopenias lasting more than 1 year but not more than 5. 

Additionally, the investigators noted that no new or unexpected adverse events were reported during long term follow-up.

“These results strengthen our confidence in CAR-T cell therapies as a truly transformative and paradigm-shifting advance in cancer care, as well as our commitment to continue developing this technology with next-generation platforms,” stated Jeff Legos, executive vice president, global head of oncology & hematology development, at Novartis.

Additional studies from Novartis’ CAR-T program presented at the 2022 EHA Congress include updates from the first-in-human dose escalation trials with PHE885 in adults with r/r multiple myeloma

 and with YTB323 in adults with r/r diffuse large B-cell lymphoma.

1. Rives S, Maude SL, Hiramatsu H, et al. Tisagenlecleucelin pediatric and young adult patients (Pts) with relapsed/refractory (R/R) B-Cell acute lymphoblastic leukemia (B-ALL): Final analyses from the ELIANA study. Presented at: 2022 Hybrid Congress of the European Hematology Association (EHA). June 9-12, 2022; Vienna, Austria. Abstract #S112

2. Novartis five-year Kymriah data show durable remission and long-term survival maintained in children and young adults with advanced B-cell ALL. News release. Novartis. June 12, 2022.https://www.novartis.com/news/media-releases/novartis-five-year-kymriah-data-show-durable-remission-and-long-term-survival-maintained-children-and-young-adults-advanced-b-cell-all

3. Sperling AS, Nikiforow S, Derman B, et. al. Phase I study data update of PHE885, a fully human BCMA-directed CAR-T cell therapy manufactured using the T-Charge™ platform for patients with relapsed/refractory (r/r) multiple myeloma (MM). Presented at: 2022 Hybrid Congress of the European Hematology Association (EHA). June 9-12, 2022; Vienna, Austria. Abstract #P1446

4. Munshi, N. et. al. Phase II study of PHE885, a B-cell maturation antigen-directed chimeric antigen receptor t-cell therapy, in adults with relapsed/refractory (r/r) multiple myeloma (MM). Presented at: 2022 Hybrid Congress of the European Hematology Association (EHA). June 9-12, 2022; Vienna, Austria. Abstract #PB1983

5. Dickinson, M. et. al. Phase I study of YTB323, a chimeric antigen receptor (CAR)-T cell therapy manufactured using T-Charge™, in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Presented at: 2022 Hybrid Congress of the European Hematology Association (EHA). June 9-12, 2022; Vienna, Austria. Abstract #S212

Among treated patients, 42% achieved 5-year event free survival.  

Tisa-Cel Shows Durable Efficacy in Pediatric and Young Adult Patients With R/R B-Cell Acute Lymphoblastic Leukemia 

Updated data from the phase 1, first-in-human study (NCT04236011) of Gracell Biotechnologies’ GC012F continues to demonstrate the 

 chimeric antigen receptor (CAR) T-cell therapy’s efficacy in relapsed/refractory multiple myeloma (R/R MM).

Results from the final dataset of 29 patients were presented at the 

 held both virtually and in Vienna, Austria, by Juan Du, professor, Changzheng Hospital, Shanghai, China.

"The updated data of the final dataset of 29 treated patients underscore the deep responses achieved with GC012F, including a 100% minimal residual disease (MRD) negativity rate in all patients treated," Martina Sersch, MD, PhD, chief medical officer, Gracell, said in a statement.

 "GC012F for the treatment of RRMM continues to demonstrate a favorable safety profile and a promising median duration of response (DOR)... in mostly high risk, heavily pretreated patients, including those with extramedullary disease and those who were previously exposed to proteasome inhibitors, immunomodulatory drugs and anti-CD38 agents.”

The multicenter study has enrolled and treated 29 patients between October 2019 and January 2022 with 1x10

 Patients had a median of 5 prior lines of therapy and most (n = 26) were categorized as high risk by mSMART 3.0 criteria. Median follow-up was 11 months (range, 4.9-34.5) and is continuing. All patients achieved MRD negativity and most (n = 22; 75.9%) achieved MRD-stringent complete responses. By dose level, DL1 had a response rate of 100 % (n = 2), DL2 had a response rate of 80% (N = 8), and DL3 had a response rate of 100% (n = 17). Median DOR was 15.7 months 95% CI, 7.6-33.1).

Exploring New Paths for CAR T-Cell Therapy Research in Multiple Myeloma

GC012F had a manageable safety profile, with some cases of low-grade cytokine release syndrome (CRS; n = 27) although there were 2 grade 3 CRS cases (7%). No cases of immune effector cell-associated neurotoxicity syndrome were observed. Final duration of response and best overall response are still being evaluated and patients continue to be monitored with some delays in follow-up due to COVID-19 related lockdowns in Shanghai.

GC012F is developed using Gracells’ FasTCAR-enabled dual-targeting CAR-T platform and simultaneously targets CD19 and BCMA to potentially improve efficacy and reduce relapse. The FDA granted orphan drug designation to the therapy in November 2021 for the treatment of MM. GC012F is also being evaluated in B-cell non-Hodgkin lymphoma (B-NHL) in another phase 1 study, data from which were presented at the EHA 2022 congress by Xinfeng Chen, adjunct professor, First Affiliated Hospital of Zhengzhou University, China.

Three patients with B-NHL have been dosed with 3x10

cells as of February 22, 2022. So far, investigators have observed a 100% complete response rate at 1 month in all patients. Two patients have maintained this CR for 3 months. All patients experienced at least grade 3 neutropenia. There was 1 case of grade 3 cytokine release syndrome (CRS) and 2 cases of grade 1 CRS. The study is continuing to enroll patients.

“In addition, we presented at EHA the first-in-human data of GC012F in B-NHL, a potential second indication. We look forward to continuing developing this lead asset and providing a new treatment option to the patients with high unmet needs,” Sersch added to the statement.

1. Du J, Jiang H, Dong B, et al. Updated results of a multicenter first-in-human study of BCMA/CD19 dual-targeting fast CAR T- GC012f for patients with relapsed/refractory multiple myeloma (RRMM). Presented at: EHA 2022 Congress, June 9-12, Vienna, Austria and virtually. Abstract #S186.
2. Gracell Biotechnologies presents updated clinical data for BCMA/CD19 dual-targeting FasTCAR GC012F in RRMM at EHA2022 Congress, highlighting 100% MRD negativity rate in all treated patients. News release. Gracell Biotechnologies. June 12, 2022. 

https://ir.gracellbio.com/news-releases/news-release-details/gracell-biotechnologies-presents-updated-clinical-data-bcmacd19


3. Chen X, Ping Y, Li L, et al. First-in-human study of CD19/BCMA dual-targeting fast CAR-T GC012f for patients with relapsed/refractory B-cell non-Hodgkin’s lymphoma. Presented at: EHA 2022 Congress, June 9-12, Vienna, Austria and virtually. Abstract #P1218.

GC012F also showed efficacy in B-cell non-Hodgkin lymphoma. 

Dual-Targeted CAR T-Cell Therapy Continues to Show Efficacy in R/R Multiple Myeloma 

Anbalcabtagene autoleucel (anbal-cel; CRC01; Curocell) has demonstrated impressive responses in patients with relapsed/refractory 

 (R/R LBCL) treated in a phase 1/2 study (NCT04836507).

Findings from the study were presented at the 

 held both virtually and in Vienna, Austria, by Wong Seog Kim, MD, PhD, Professor, Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.

"Although CD19 directed CAR-T therapy changed the treatment paradigm for Large B-cell lymphoma, which is one of the most aggressive hematologic malignant cancer, more than 50% of LBCL patients didn't experience the clinical benefit of CD19 CAR-T treatment, and there are still huge unmet medical needs. Anbal-cel's phase 1 study result demonstrates the OVISTM platform's potential to maximize CAR-T's functionality to eradicate tumors,” Gunsoo Kim, MS, chief executive officer, Curocell, said in a statement.

The dose-escalation study is evaluating the safety and preliminary efficacy of anbal-cel in patients with R/R LBCL.

 The study has dosed 11 patients with R/R diffuse LBCL who had received 2 or more prior lines of therapy, 4 of which (36%) had received at least 4 prior lines of therapy. Patients were dosed with 2x10

 cells/kg (DL3) after 3 days of cyclophosphamide (500mg/m

Liso-Cel Yields High Response Rates and Positive PROs in LBCL

Anbal-cel is a CD-19 targeted chimeric antigen receptor (CAR) T-cell therapy integrated with Curocell’s OVISTM (Overcome Immune Suppression) platform. The platform allows the cell therapy to be knocked-down for both PD-1 and TIGIT receptors.

Overall, Kim and colleagues that 9 patients responded with a complete response (CR), for an overall response rate (ORR) and CR rate of 82%. Three patients treated in DL1 had CRs and these responses have lasted for over 12 months in 2 patients. All patients dosed in DL3 have achieved a CR.

No patients experienced dose-limiting toxicities and the maximum tolerated dose was not reached. About half of the patients (n = 5; 46%) experienced cytokine release syndrome (CRS). These cases were mostly mild (grade 1 or 2; n = 3; 27%) but 2 patients (18%) had grade 3 CRS. CRS onset took a median of 7 days (range, 1-16) and lasted a median of 5 days (range, 1-19).

One patient in DL3 experienced grade 2 immune effector cell-associated neurotoxicity syndrome which onset 7 days after infusion and lasted for 13 days. This patient had central nervous system involvement prior to the study. Other common grade 3/4 treatment-related adverse events included anemia (n = 2; 18%), neutropenia (n = 2; 18%), and thrombocytopenia (n = 2; 18%).

Investigators observed dose-dependent expansion of the cell therapy with peaks at 15.4 days in DL1, 15.8 days in DL2, and 14.5 days in DL3. Median maximal expansion and exposure during the first 28 days following infusion also proportionally increased according to dose. A phase 2 trial of anbal-cel has now commenced and patient enrollment is ongoing based on the promising phase 1 study data.

“We are very excited about this promising clinical result even though the patient number treated with anbal-cel is limited with a total of 11 and looking forward to the ongoing phase 2 clinical trial to confirm the efficacy and safety of anbal-cel. Furthermore, we believe these data represent the excellence of our next-generation CAR-T technology,” Kim added.

1. Kim WS, Kim SJ, Yoon SE, et al. Phase 1/2 study of anbal-cel, novel anti-CD19 CAR-t therapy with dual silencing of PD-1 and TIGIT in relapsed or refractory large B cell lymphoma. Presented at: EHA 2022 Congress, June 9-12, Vienna, Austria and virtually. Abstract #S214.
2. Curocell announced impressive CR rate in Phase 1 study with anbal-cel, the next generation CD19 CAR-T integrated OVIS™ platform. News release. Curocell. June 13, 2022. https://www.biospace.com/article/releases/curocell-announced-impressive-cr-rate-in-phase-1-study-with-anbal-cel-the-next-generation-cd19-car-t-integrated-ovis-platform/

The CD-19 CAR T-cell therapy is developed using Curocell’s OVISTM platform. 

Anbal-Cel Shows Promising Responses in Large B-Cell Lymphoma 

Exagamglogene autotemcel (exa-cel; CTX001; 

CRISPR Therapeutics/Vertex Pharmaceuticals)

 eliminated the need for transfusion in treated patients with transfusion-dependent β-thalassemia (TDT) as well as vaso-occlusive crises (VOCs) in patients with sickle cell disease (SCD).

Results from the phase 2/3 CLIMB THAL-111 (NCT03655678) and CLIMB SCD-121 (NCT03745287) studies were presented in a late-breaker at the 

 held both virtually and in Vienna, Austria, by Franco Locatelli, MD, PhD, professor of pediatrics, University of Pavia, and head, pediatric hematology and oncology, IRCCS Ospedale Bambino Gesù, Rome.

During his presentation, Locatelli explained that “patients with hereditary persistence of hemoglobin F (HbF), despite the fact that they inherit the sickle cell or beta thalassemia gene, do not develop the clinical signs of these conditions because of the increase of HbF... the line of reasoning [behind exa-cel] is that inactivating the BCL11A gene with the CRISPR/Cas9 genome editing approach would inactivate the production of BCL11A,” which deactivates HbF production.

Locatelli discussed results from the 75 patients that have received exa-cel treatment as of February 2022, 44 with TDT enrolled in the CLIMB THAL-111 trial and 31 with SCD enrolled in the CLIMB SCD-121 trial. Both trials are international multi-center, open-label, single-arm studies. 

Bluebird Bio's Beti-Cel Gains Unanimous Support of Benefit in β-thalassemia

CLIMB THAL-111's primary endpoint is proportion of patients maintaining a weighted average Hb of at least 9 grams per deciliter without red blood cell transfusion for at least 12 consecutive months after infusion. CLIMB SCD-121's primary endpoint is proportion of patients who have not experienced a severe VOC for at least 12 consecutive months after infusion. Both trials are assessing engraftment, total Hb, HbF, BCL11A edited alleles, transfusions, and adverse events (AEs).

Of patients with TDT, 42 (95%) reached transfusion independence (follow-up, 0.8-36.2 months), with the remaining 2 patients achieving a 75% and 89% reduction in transfusion volume. All patients (100%) with SCD became free of VOCs (follow-up, 2.0-32.3 months).

No participants in the CLIMB-SCD-121 study developed serious AEs related to exa-cel and safety profile was consistent with that of busulfan myeloablation conditioning and autologous hematopoietic stem cell transplantation. Two participants in the CLIMB-THAL-111 study did develop SAEs related to exa-cel, 1 participant developed idiopathic pneumonia syndrome, hemophagocytic lymphohistiocytosis, acute respiratory distress syndrome, and headache, while the other developed delayed neutrophil engraftment and thrombocytopenia. All SAEs have resolved.

“In conclusion the data from these 75 patients with either TDT or SCD show that a single dose of exa-cel leads to early increases in HbF total Hb that are sustained over time. Thus, we conclude that exa-cel has the potential to be the first CRISPR/Cas9 therapy to provide a functional cure for patients with thalassemia or SCD,” Locatelli concluded.

Locatelli F, Frangoul H, Corbacioglu S, et al. Efficacy and safety of a single dose of CTX001 for transfusion-dependent βeta-thalassemia and severe sickle cell disease. Presented at: EHA 2022 Congress, June 9-12, Vienna, Austria and virtually. Late-breaker 2367.

Results from the CLIMB THAL-111 and CLIMB SCD-121 trials were presented at the EHA 2022 Congress. 

Exa-Cel Eliminates Transfusions in TD Thalassemia and VOCs in Sickle Cell Disease 

(axi-cel; Yescarta; Kite Pharma) appears to be more efficacious but with a higher toxicity profile than tisagenlecleucel (tisa-cel; Kymriah’ Novartia) in patients with diffuse large B-cell lymphoma (DLBCL).

 held both virtually and in Vienna, Austria, by Emmanuel Bachy, MD, PhD, Hospices Civils de Lyon, France.

“Axi-cel and tisa-cel have both demonstrated impressive clinical activity in R/R DLBCL. In a previous propensity score matching (PSM) analysis (Bachy et al., ASH 2021) allowing for balanced comparison between axi-cel and tisa-cel outcomes, we reported on a prolonged progression-free survival (PFS) but a higher toxicity associated with axi-cel compared with tisa-cel. No overall survival (OS) difference was observed but the follow-up was short (6 months),” Bachy and colleagues wrote.

Bachy and colleagues analyzed data from 809 patients with R/R DLBCL, at least 2 prior lines of therapy, and prior chimeric antigen receptor (CAR) T-cell therapy with either tisa-cel or axi-cel from 25 French centers part of the DESCAR-T registry. Patients included in the study were treated between July 2018 and October 2021. Of these patients, 60 were not infused due to progression or death and 20 for other reasons, leaving 729 to proceed to lymphodepletion and CAR-T infusion.

Axi-Cel Superior to SOC in Elderly Patients with Diffuse Large B-Cell Lymphoma

The investigators used PSM to create a balanced covariate distribution between patients treated with tisa-cel and axi-cel. Covariates included age, sex, LDH level, C reactive protein, time between last treatment and infusion, ECOG performance status, Ann Arbor stage, prior lines of treatment, bridging and response to bridging, prior stem cell transplant, and others.

In a matched population of 209 patients treated with tisa-cel and 209 patients treated with axi-cel, best overall response rate (ORR) was 66% with tisa-cel and 80% with axi-cel and best complete response (CR) rate was 42% with tisa-cel and 60% with axi-cel (

 <.001 for both). One-year progression-free survival (PFS) rate was 33% for tisa-cel and 47% for axi-cel (hazard rate [HR], 1.65 [95% CI, 1.26-2.18]; 

 = .0003) after a median follow-up of 11.7 months (95% CI, 10.5-12.0). One-year OS was 49% with tisa-cel and 63% with axi-cel (HR, 1.58 [95% CI, 1.13-2.21; 

 = .0072). Inverse Probability Treatment Weighting confirmed these findings.

In terms of safety, patients treated with axi-cel were more likely to experience grade 1 or 2 cytokine release syndrome (CRS; 

 = .004) but were not significantly more likely to experience grade 3 or higher CRS (9% vs 5%; 

 =.130). Patients treated with axi-cel were more likely to experience all grades of immune effector cell-associated neurotoxicity syndrome (ICANS; 48% vs 22%), with 29 patients (14%) treated with axi-cel experiencing at least grade 3 ICANS compared to 6 patients (3%) treated with tisa-cel.

“In conclusion, our matched-comparison study supports a higher efficacy but also a higher toxicity of axi-cel compared with tisa-cel in third or more treatment line for R/R DLBCL,” Bachy and colleagues concluded.

Bachy E, Le Gouill S, Sesques P, et al. A matched comparison of tisagenlecleucel and axicabtageneciloleucel car t cells in relapsed or refractory diffuse large b-cell lymphoma: A real-life Lysa study from the French DESCAR-T registry. Presented at: EHA 2022 Congress, June 9-12, Vienna, Austria and virtually. Abstract #S260.

Response rates were significantly higher but patients had more cases of ICANS and CRS with axi-cel treatment compared to tisa-cel treatment. 

Axi-Cel More Efficacious With Higher Toxicity Than Tisa-Cel in Diffuse Large B-Cell Lymphoma 

This article was originally published on our sister site, 

ARI0002H, a BCMA-directed CAR T-cell therapy, achieved promising response rates in patients with relapsed/refractory multiple myeloma, according to findings from a phase 1/2 trial (NCT04309981) presented at the 

2022 European Hematology Association (EHA) Annual Meeting

At a median follow-up of 17.5 months (range, 5-23), ARI0002H elicited a response in 100% of patients (n = 30), including a complete remission (CR) in 63% of patients and a very good partial response (VGPR) or better in 93% of patients. Additionally, 96% of patients were minimal residual disease (MRD) negative at 28 days, and 92% were MRD negative at 100 days. At 6 months, 74% of patients were MRD negative, and at 12 months, 69% of patients were MRD negative.

“ARI0002H production is fast and feasible. We see 11 days in time of production. Patients achieved a sustained response with low-grade toxicity,” lead study author Carlos Fernández de Larrea, MD, PhD, a hematologist at the Hospital Clínic de Barcelona, and an associate professor at the University of Barcelona, said in a presentation of the data.

ARI0002H is an academic lentiviral autologous second-generation CAR T-cell therapy with a 4-1BB co-stimulatory domain and a humanized single chain variable fragment targeting BCMA.

The phase 1/2 trial evaluated the safety and efficacy of ARI0002H in patients with relapsed/refractory multiple myeloma who received prior treatment with a proteasome inhibitor, an immunomodulatory drug, and/or an anti-CD38 monoclonal antibody.

“Even though the prognosis has improved significantly in the last year, [patients with refractory multiple myeloma] don’t have a clear standard of care, and they have a poor survival,” Fernández de Larrea said.

The trial enrolled patients between the ages of 18 and 75 years with a diagnosis of multiple myeloma measurable by monoclonal component in serum and/or urine, or by free light chains in serum according to the eligibility criteria for clinical trials of the International Myeloma Working Group. Other eligibility criteria included at least 2 prior lines of treatment, being refractory to the most recent line of treatment, an ECOG performance status between 0 and 2, and a life expectancy of more than 3 months.

Key exclusion criteria included allogeneic stem cell transplant within 6 months prior to inclusion or graft-vs-host disease that required active systemic immunosuppressive treatment; an absolute lymphocyte count less than 0.1 x 10

/L; previous neoplasia, except in patients who have been in complete remission for more than 3 years, except for cutaneous carcinoma (non-melanoma); active infection requiring treatment; active infection of HIV, HBV, or HCV; previous diagnosis of symptomatic primary amyloidosis; and contraindication to receive conditioning chemotherapy.

Enrolled patients received conditioning chemotherapy consisting of 30 mg/m

 of cyclophosphamide per day, starting at 6 days prior to CAR T-cell infusion. At day 0, patients started fractionated dosing of ARI0002H at 0.3 x 10

/kg CAR+ cells. From month 4 on, patients who achieved a response, did not progress, and did not experience complications to treatment were eligible for a second dose of ARI0002H, up to 3.0 x 10

Prior data with ARI0001 showed that fractionated dosing reduced toxicity and maintained efficacy. In patients administered a single dose of 3.0 x 10

/kg CAR+ cells, cytokine release syndrome (CRS) of any grade occurred in 73.3% of patients compared with 43.5% of patients who received fractionated dosing. Instances of grade 3 or higher CRS occurred in 26.7% of patients who received a single dose of therapy vs 4.3% of patients who received a fractionated dose of treatment.

The primary end points of the trial were overall response rate (ORR) and safety, specifically the rate of CRS.

A total of 35 patients enrolled in the trial, and 30 patients received treatment. Four patients could not receive ARI0002H due to disease progression prior to apheresis (n =2) or study treatment (n = 2), and 1 patient died of a fungal infection.2

The median age of evaluable patients was 61 years (range, 36-74), and 18 patients were male. Additionally, 47%, 23%, and 23% of patients had heavy chain isotype of IgG, IgA, and Bence Jones, respectively, and 50% of patients each had light chain isotype of kappa and lambda. Furthermore, 47% of patients has plasmacytomas, including 20% with extramedullary plasmacytomas, and 33% had high-risk cytogenetics. The median serum M-protein was 12.5 g/L (range, 0-90), the median differential serum free light chains was 443 mg/L (range, 4-7325), the median urine M-protein was 0.08 g/24 hours (range, 0-19), and the median percentage of bone marrow plasma cells was 11% (range, 0%-100%).

The median prior lines of therapy for enrolled patients was 4 (range, 2-10), and 87% of patients received prior autologous stem cell transplant, 13% had prior allogeneic stem cell transplant, 100% of patients were triple exposed, and 67% of patients were triple refractory to a proteasome inhibitor (bortezomib [Velcade] or carfilzomib [Kyprolis]), an immunomodulatory drug (lenalidomide [Revlimid] or pomalidomide [Pomalyst], and an anti-CD38 monoclonal antibody (daratumumab [Darzalex]).

Twenty-four patients received the full fractionated dose of 3.0 x 10

/kg CAR+ cells at first infusion, and 6 patients received 1.2 x 10

/kg CAR+ cells. Additionally, 24 patients were administered a second dose, including 19 who received 3.0 x 10

/kg CAR+ cells, 3 who were given 1.8 x 10

/kg CAR+ cells, and 2 patients who had 1.2 x 10

Additional data showed that 73% of patients were still alive after 18 months, including 53% of patients without disease progression. The median progression-free survival (PFS) and overall survival (OS) were not reached.

In patients with plasmacytomas, the ORR was 93%, including a CR rate of 57% and a VGPR rate of 29%. One patient had a partial response, and 1 patient had progressive disease.

After the first infusion of ARI0002H, the median maximum peripheral blood expansion was 14 days (range, 7 days–6 months). At day 100, 6 months, and 12 months, the median rate of CAR+ cells in peripheral blood was 62%, 36%, and 20%, respectively. The median persistence of CAR+ cells was 5 months (range, 2–not reached). Notably, 33% of patients who relapsed (n = 3 of 9) had detectable CAR+ cells in peripheral blood.

Of the 24 patients who received a second dose of ARI0002H, 9 were given a lymphodepletion regimen. Notably, 58% of patients already had a stringent complete response at reinfusion, 25% had improved response after reinfusion, and 17% maintained response after reinfusion.

Regarding safety, 90% of patients experienced CRS, though no instances of grade 3 or higher events were reported. Specifically, 67% of patients experienced grade 1 CRS, and 23% had grade 2 CRS. The median time to onset of CRS was 8 days (range, 1-10), and the median duration of CRS was 4 days (range, 1-12). Notably, 74% of patients received tocilizumab (Actemra), primarily for persistent grade 1 CRS, and 10% received corticosteroids. No instances of CRS were reported in patients who received a second infusion.

Fernández de Larrea said there were no reported cases of neurotoxicity. Notably, 87% of patients experienced any grade of neutropenia, including 69% who had grade 3 or 4 events. The median duration was 9 months (range, 1-19). Additionally, 100% of patients had grade 3 or 4 thrombocytopenia with a median duration of 4 months (range, 0-14), and 90% of patients had anemia of any grade, including 52% that was classified as grade 3 or 4. The median duration of anemia was 5 months (range, 0-20). Notably, all patients presented with cytopenias at least 30 days after infusion (thrombocytopenia, 100%; neutropenia, 93%; anemia 93%).

Other notable adverse effects of any grade included macrophage-activation syndrome (n = 3), hepatitis B reactivation (n = 1), and colon cancer (n = 1).

For more coverage of EHA 2022, click here. 

Fernández de Larrea C. Efficacy and safety of ARI0002H, an academic BCMA-directed CAR-T cell therapy with fractionated initial therapy and booster dose in patients with relapsed/refractory multiple myeloma. Presented at: 2022 EHA Congress; June 9-17, 2022; Vienna, Austria. Abstract S103.

Fernández de Larrea C, Gonzalez-Calle V, Cabañas V, et al. Results from a pilot study of ARI0002H, an academic BCMA-directed CAR-T cell therapy with fractionated initial infusion and booster dose in patients with relapsed and/or refractory multiple myeloma. 

 2021;138(suppl 1):2837. doi:10.1182/blood-2021-147188

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. Updated February 4, 2022. Accessed June 11, 2022. 

https://clinicaltrials.gov/ct2/show/NCT04309981

Participants in the trial achieved a sustained response and experienced low-grade toxicity. 

Lentiviral CAR T Therapy Delivers Good Efficacy, Safety in R/R Multiple Myeloma

Results of a phase 1 clinical trial investigating the safety and feasibility of a refined anti-CD30 CAR T-cell therapy are promising, demonstrating good cell persistence up to 11 months post-infusion and a good safety profile.

, June 9-17, 2022, in Vienna, Austria and virtual, by investigator Ana Carolina Caballero, of the department of hematology at the Hospital de la Santa Creu I Sant Pau in Barcelona, Spain.

A research group consisting of Caballero and her colleagues developed a novel CD30 CAR T by using a targeted epitope within the non-cleavable part of the CD30 receptor and memory stem T cells in hopes of improving engraftment, cell persistence, and antitumor activity.

Results of a preclinical study published in 2021 in 

 by Carmen Alvarez-Fernandez, et al, demonstrated good cell expansion ex vivo and good persistence and immunity in a mouse model of Hodgkin lymphoma, which was completely eradicated in vivo. In addition, the CAR T therapy showed greater tumor infiltration and an enhanced antitumor effect in vivo.

In this first in human, phase 1/2a dose escalation clinical trial (NCT04653649), Caballero and colleagues enrolled 11 patients (median age, 49.9 years) with relapsed/refractory Hodgkin lymphoma or CD30+ T-cell non-Hodgkin lymphoma, 10 of whom ultimately received treatment with HSP-CAR30. Primary end points were safety and to establish max tolerated dose for phase 2, with response rates among secondary end points.

Patients had received a median of 4.6 prior lines of treatment. Following leukapheresis, 3 patients received dose-level 1 (3x10

 /kg), and 4 received dose-level 3 (10x10

 /kg). Prior to infusion, patients with HL underwent lymphodepletion with fludarabine/bendamustine and those with T-NHL received ludarabine/cyclophosphamide. Mean HSP-CAR30 expression was 94.79±3.38% (±SD). Memory T-cell subset comprised 93.07±4.8% (±SD) in CD4+ and 91.64±4.9% (±SD) in CD8+. Peak levels of HSP-CAR30 cells were reached at a mean of 29 days post-infusion and were detectable via flow cytometry up to 11 months post-infusion.

Notably, no dose-limiting toxicities were observed and the therapy was generally well tolerated. Sixty percent of patients developed grade 1 cytokine release syndrome and 40% developed skin rash. In addition, 4 infections occurred, including a grade 4 case of pulmonary tuberculosis; grade 3 CMV pneumonia in a patient with a history of cytomegalovirus; grade 1 rhinovirus; and grade 1 COVID-19. No cases of neurotoxicity or immune effector cell-associated neurotoxicity syndrome (ICANS) were observed. Grade 3 and 4 cytopenias included anemia (5/10), thrombopenia (3/10), neutropenia (8/10), and long-lasting cytopenias (2/10). Notably, no non-relapse mortality events occurred.

In terms of efficacy, 100% of treated participants reached objective response, with 50% of the total cohort reaching complete response (CR) and 62% of patients with HL reaching CR. Three patients (2 with T-NHL and 1 with HL) succumbed to progressive disease. One patient with HL that achieved partial response with relapse at 6 months received treatment with nivolumab to again reach partial response, and received a second infusion of HSP-CAR30 between 13-14 months after initial treatment. Follow-up data is available through 14 months, with longest CR at data cutoff at 12 months.

Based on the significant antitumor efficacy observed and the good safety profile, a phase 2 study has begun examining the safety and efficacy of dose level 2 (5x10

1. Caballero AC, Escriba-Garcia L, Montserrat-Torres R, et al. A phase 1, first-in-human, dose-escalation clinical trial of memory-enriched CD30-CAR T-cell therapy for the treatment of relapsed or refractory Hodgkin lymphoma and CD30+ T-cell lymphoma. Presented at: European Hematology Association Annual Meeting. June 9-17, 2022; Vienna, Austria, and virtual. S257.

2. Alvarez‐Fernández C, Escribà‐Garcia L, Caballero A, et al. Memory stem T cells modified with a redesigned CD30‐chimeric antigen receptor show an enhanced antitumor effect in Hodgkin lymphoma. Clin Transl Immunol. 2021;10(4). doi:10.1002/cti2.1268

A phase 2 clinical trial evaluating a T-cell memory enriched anti-CD30 CAR-T is now underway. 

Conferences

T-Charge CAR T-Cell Therapy Shows Efficacy in Multiple Myeloma

CTX130 Shows Acceptable Safety Profile, Clinically Meaningful Responses in R/R T-Cell Lymphoma

CAR T-Cell Therapy Yields High Response Rates in Follicular Lymphoma

Tisa-Cel Shows Durable Efficacy in Pediatric and Young Adult Patients With R/R B-Cell Acute Lymphoblastic Leukemia

Dual-Targeted CAR T-Cell Therapy Continues to Show Efficacy in R/R Multiple Myeloma

Anbal-Cel Shows Promising Responses in Large B-Cell Lymphoma

Exa-Cel Eliminates Transfusions in TD Thalassemia and VOCs in Sickle Cell Disease

Axi-Cel More Efficacious With Higher Toxicity Than Tisa-Cel in Diffuse Large B-Cell Lymphoma

Lentiviral CAR T Therapy Delivers Good Efficacy, Safety in R/R Multiple Myeloma

CD30-Targeted CAR T Cell Therapy Promising in Heavily Pretreated Hodgkin Lymphoma