Victoria Johnson

The FDA has approved Bristol Myers Squibb’s supplemental biologics license application for 

 (liso-cel; Breyanzi) as second-line therapy for patients with large B-cell lymphoma (LBCL).

The chimeric antigen receptor (CAR) T-cell therapy was originally approved in February 2021 for adults with relapsed or refractory diffuse LBCL who have not responded to at least 2 other treatments based off data from the pivotal 

In the second-line setting, liso-cel recently showed good efficacy and patient-reported outcome (PRO) data in the 

(NCT03483103), updated data from which were presented at the 

2022 American Society of Clinical Oncology (ASCO) meeting, held June 3-7, 2022, in Chicago, Illinois

The TRANSCEND study dosed 61 participants that had disease that relapsed after or was refractory to first-line chemotherapy. These participants were followed-up for a median of 12.3 months (range, 1.2–26.5). Investigators found that overall response rate (ORR) was 80% and complete response rate (CR) was 54%. Median duration of response (DOR) was 12.1 months, progression-free survival (PFS) was 9.0 months, and median overall survival (OS) has not been reached.

Frederick Locke, MD, on the Impact Potential of CAR T-Cell Therapies in Hematologic Malignancies

Investigators assessed PROs and found that completion rates were high (≥ 80%) across most visits for all measures. Baseline European Organisation for Research and Treatment of Cancer Quality of Life of Cancer Patients (EORTC QLQ-C30) mean fatigue scores were worse by at least 10 points at baseline compared to a general noncancer population. These scores, along with pain domain scores, Functional Assessment of Cancer Therapy – lymphoma subscale, and EuroQol Visual Analogue Scale scores improved significantly by least square means through day 545. 

Patients also reported that lymphoma symptoms improved in a clinically meaningful way. No outcomes significantly worsened and 70% of patients demonstrated meaningful improvement in FACT-LymS at month 6. 

Liso-cel has been well-tolerated, with treatment-emergent adverse events (TEAE) in TRANSCEND that included neutropenia (51%), fatigue (39%), and CRS (38%), including 1 case of grade 3 CRS (2%). Neurological events occurred in 31% of participants, 5% (n = 3) of which were grade 3 cases. AEs resolved with the use of tocilizumab (7%), corticosteroids (3%), or both (20%). Overall, grade 3 TEAEs occurred in 79% of participants, with grade 5 cases in 2 patients due to COVID-19. Two patients (3%) had grade 3/4 infections and 15 (25%) had at least grade 3 neutropenia at Day 29.

Liso-cel's supplemental biologics license application 

 in April 2022 for the treatment of relapsed/refractory DLBCL, primary mediastinal large B-cell lymphoma (PMBCL), and follicular lymphoma grade 3B (FL3B) in patients who have received 2 or more lines of systemic treatment.

1.U.S. FDA Approves Bristol Myers Squibb’s CAR T Cell Therapy Breyanzi® for Relapsed or Refractory Large B-cell Lymphoma After One Prior Therapy. News release. Bristol Myers Squibb. June 24, 2022. https://news.bms.com/news/details/2022/U.S.-FDA-Approves-Bristol-Myers-Squibbs-CAR-T-Cell-Therapy-Breyanzifor-Relapsed-or-Refractory-Large-B-cell-Lymphoma-After-One-Prior-Therapy/default.aspx
2. FDA Approves New Treatment For Adults With Relapsed Or Refractory Large-B-Cell Lymphoma. News release. FDA. February 5, 2021. https://www.prnewswire.com/news-releases/fda-approves-new-treatment-for-adults-with-relapsed-or-refractory-large-b-cell-lymphoma-301223275.html
3. Sehgal A, Hoda D, Riedell PA, et al. Lisocabtagenemaraleucel (liso-cel) as second-line (2L) therapy for R/R large B-cell lymphoma (LBCL) in patients (pt) not intended for hematopoietic stem cell transplantation (HSCT): Primary analysis from the phase 2 PILOT study. Presented at: 2022 ASCO Annual Meeting, June 3-7, 2022, Chicago, Illinois. Abstract #7062
4. Gordon LI, Hoda D, Shi L, et al. Lisocabtagenemaraleucel (liso-cel) as second-line (2L) treatment (tx) for R/R large B-cell lymphoma (LBCL) in patients (pt) not intended for hematopoietic stem cell transplantation (HSCT): Patient-reported outcomes (PRO) from the phase 2 PILOT study. Presented at: 2022 ASCO Annual Meeting, June 3-7, 2022, Chicago, Illinois. Abstract #6567
5. US Food and Drug Administration (FDA) accepts for priority review Bristol Myers Squibb’s supplemental biologics license application for Breyanzi (lisocabtagenemaraleucel) as a second-line therapy for relapsed or refractory large B-cell lymphoma. News release. Bristol Myers Squibb; February 17, 2022. Accessed February 17, 2022. 


6. Bristol Myers Squibb receives European Commission approval for CAR T cell therapy Breyanzi (lisocabtagenemaraleucel) for certain forms of relapsed or refractory large B-cell lymphoma. News release. Bristol Myers Squibb. April 5, 2022. Accessed April 8, 2022. https://bit.ly/3LPwb0l

Articles

The approval builds off of liso-cel's (Breyanzi) previous indication for third-line or later treatment in LBCL.

Liso-Cel Approved for Second-Line Large B-Cell Lymphoma 

The EMA’s Committee for Medicinal Products for Human Use (CHMP) has given a positive opinion to BioMarin’s valoctocogene roxaparvovec (val-rox; Roctavian) gene therapy for the potential treatment of 

"Today's positive CHMP opinion for Roctavian addresses the unmet medical needs in severe hemophilia A by providing a treatment option that has been shown in clinical studies can maintain effective levels of endogenously produced coagulation Factor VIII over multiple years with a single intravenous administration. Currently available treatment options require long-term, chronic use with a high degree of compliance to a prescribed schedule to be effective," Hank Fuchs, MD, president, worldwide research and development, BioMarin, said in a statement.

A final decision on val-rox's approval is expected from the European Commission in the third quarter of 2022. Meanwhile, in the US, the filing of BioMarin’s biologic license application was 

 with the FDA requesting additional durability and safety data on the gene therapy.

 The BLA was previously rejected in August 2020 with requests for 2-year follow-up data.

BioMarin is working to collect the new data from ongoing trials, including GENEr8-1 (NCT03370913), GENEr8-3 (NCT04323098), and the non-clinical study GENEr8, and plans to resubmit the BLA by the end of September 2022 instead of June.

Steven W. Pipe, MD, on Challenges in Gene Therapy Trials for Hemophilia

"The positive CHMP opinion offers hope for a new treatment option for people with severe hemophilia A, who have been bound to lifelong treatment and still experience serious health complications, such as breakthrough bleeding, pain, and joint damage, as well as having to constantly consider their condition in all aspects of their lives," Johannes Oldenburg, MD, PhD, director, Institute of Experimental Haematology and Transfusion Medicine and Haemophilia Centre, University Clinic, Bonn, Germany, added to the statement.

 "The robust data set from the clinical trial program underscores the potential impact of gene therapy for patients, including a substantial and sustained reduction in bleeding that would have previously required Factor VIII infusions."

In March 2022, BioMarin announced the publication of results from the GENEr8-1 study in the 

 that demonstrated val-rox's ability to 

restore endogenous factor VIII production

 and significantly reduce bleeding and use of enzyme replacement therapy in patients with hemophilia A.

Investigators found that 132 human immunodeficiency virus–negative participants in GENEr8-1 had mean chromogenic substrate factor VIII activity levels during weeks 49 through 52 were 42.9 IU per deciliter (standard deviation [SD], 45.5) and median chromogenic substrate factor VIII activity levels were 23.9 IU per deciliter (interquartile range [IQR], 11.9-62.3). The mean change in factor VIII activity from baseline was 41.9 IU per deciliter (95% CI, 34.1-49.7; 

 <.001) and median change was 22.9 IU per deciliter (IQR, 10.9-61.3). Val-rox's safety profile was manageable, with all participants experiencing at least 1 mild adverse event (AE) and 5 participants experiencing treatment-related serious AEs.

1. BioMarin receives positive CHMP opinion in Europe for valoctocogene roxaparvovec gene therapy to treat adults with severe hemophilia A. News release. BioMarin. June 24, 2022. 

https://investors.biomarin.com/2022-06-24-BioMarin-Receives-Positive-CHMP-Opinion-in-Europe-for-Valoctocogene-Roxaparvovec-Gene-Therapy-to-Treat-Adults-with-Severe-Hemophilia-A


2. BioMarin delays hemophilia a therapy valoctocogene roxaparvovec filing as FDA calls for more data. News release. BioMarin. May 31, 2022. 

https://www.biospace.com/article/fda-needs-more-data-for-biomarin-s-hemophilia-a-therapy/


3. Ozelo MC, Mahlangu J, Pasi J, et al. Valoctocogene roxaparvovec gene therapy for hemophilia A. 

. 2022; 386: 1013-1025. doi: 10.1056/NEJMoa2113708

BioMarin received a positive CHMP opinion after the FDA delayed val-rox's BLA filing for the second time. 

Val-Rox Approval Favored in Europe, Stalled in US

Krystal Biotech has submitted a biologics license application (BLA) for B-VEC (beremagene geperpavec), its gene therapy for the potential treatment of dystrophic epidermolysis bullosa (DEB).

The BLA submission is based off positive data from the phase 1/2 GEM-1/2 study (NCT03536143) and the 

 (NCT04491604). Positive data from the GEM-3 study were recently presented at the American Academy of Dermatology (AAD) 2022 Annual Meeting, March 25-29, Boston, Massachusetts, by principal investigator M. Peter Marinkovich, MD, associate professor, department of dermatology, Stanford University.

“The unmet medical need for DEB patients remains very high and our relentless pursuit of a treatment for this disease continues with the same sense of urgency that we have always had since the founding of Krystal Biotech,” Suma Krishnan, president, research & development, Krystal, said in a statement.

 “We look forward to working with the FDA in its review of our BLA submission.”

B-VEC is a topical, re-dosable gene therapy. It is directly applied to DEB wounds and delivers 2 copies of the COL7A1 gene directly to the skin to make functional COL7 protein. Krystal plans to submit a marketing authorization application with the EMA in the second half of 2022.

Assessing Gene Therapy in Recessive Dystrophic Epidermolysis Bullosa

The GEM-1/2 trial was a single-center, randomized, intra-patient placebo-controlled, open-label trial that enrolled 9 patients with dystrophic epidermolysis bullosa patients evaluated over 12 weeks. The trial met both its mechanistic and clinical endpoints and investigators found that B-VEC was well-tolerated with no serious treatment-related adverse events (AEs).

Recently in the GEM-3 study, investigators found that a significantly greater proportion of wounds treated with B-VEC exhibited complete wound healing compared with placebo at 3 months (absolute difference, 50.3% [95% CI, 28.7-72.0]; 

 <.005) and 6 months (absolute difference, 45.8% [95% CI, 23.6-68.0%]; 

 Almost half (49.7%) of wounds treated with B-VEC were completely healed at both 3 and 6 months compared with 7.1% of wounds treated with placebo, demonstrating durability of response. Most wounds (66.7%; n = 14) closed at 3 months were also closed at 6 months, compared with 33.3% of placebo-treated wounds meeting the same endpoint (

Pain and patient-reported outcome data were also positive, with a significant change from baseline in pain response at week 22 (

 = .02), and near-significant changes at weeks 24 (

 = .06). There was also a trend toward decreased pain in B-VEC versus placebo treated wounds. Improvements from baseline were also seen in patient-reported outcome measures such as EQ-5D-5L and Skindex-29. Safety findings were similar between GEM-1/2 and GEM-3, and the therapy continues to be well-tolerated.

“It’s the very first topical gene replacement therapy in dermatology... We've seen success in the phase 3 trial and it may be the case that more dermatologists will be seeing these patients come in since the therapy is so easy to do,” Marinkovich said in an 

1. Krystal Biotech submits biologics license application to U.S. FDA seeking approval of B-VEC for the treatment of patients with dystrophic epidermolysis bullosa. News release. Krystal Biotech. June 22, 2022. 

https://ir.krystalbio.com/news-releases/news-release-details/krystal-biotech-submits-biologics-license-application-us-fda


2. Marinkovich MP, Gonzalez ME, Guide S, et al. GEM-3: A phase 3 study of beremagene geperpavec (B-VEC), an investigational, topical gene therapy, for the treatment of dystrophic epidermolysis bullosa (DEB). Presented at: AAD 2022 Annual Meeting, March 25-29, Boston, Massachusetts.

B-VEC recently showed efficacy in the phase 3 GEM-3 trial. 

Krystal Seeks Approval for Dystrophic Epidermolysis Bullosa Gene Therapy 

AMT-130, uniQure’s gene therapy candidate for Huntington disease (HD), has been 

 with promising biomarker activity, according to updated data from the low-dose cohort of a phase 1/2 clinical trial (NCT04120493).

 vg AMT-130 in the trial showed reductions in cerebrospinal fluid (CSF) neurofilament light (NfL), with levels near or below baseline at 12 months. Participants also exhibited a mean decrease of mutant Huntingtin protein (mHTT) of 53.8% from baseline at 12 months post-treatment (range, 44-71).

“We are encouraged by this 12-month update on the patients enrolled in the low-dose cohort,” Ricardo Dolmetsch, PhD, president of research and development, uniQure, said in a statement. “Thus far in the clinical trial, AMT-130 has been well-tolerated, with no serious adverse events related to the gene therapy and NfL levels approaching baseline. We are also pleased to observe trends suggesting target engagement that are supported by the lowering of mHTT protein in evaluable patients receiving AMT-130. We look forward to presenting additional clinical data, including functional outcomes, on all patients from this important study next year.”

The low-dose cohort of the phase 1/2 trial has enrolled 10 patients with HD, 6 of which were treated with AMT-130 and 4 of which received sham surgery. Patients’ ages ranged from, 24 to 58 years and 4 were male and 6 were female. All participants were clinically diagnosed with early-stage HD with CAG repeats between 40-44, baseline Total Functional Capacity scores of 10-13, and Total Motor Scores of 7-23. Demographics were similar between treatment and sham arms.

New Gene Therapy Collaboration Targets Huntington Disease

At 12 months, all patients were evaluable for NfL measurements while 4 treated and 1 control patient were evaluable for CSF mHTT measurements (other participants did not have a measurable baseline value).

AMT-130 was generally well-tolerated in this cohort. There were no serious, treatment-related adverse events (AEs). Two serious AEs unrelated to treatment, deep-vein thrombosis and transient post-operative delirium, did occur. These AEs resolved with anticoagulants and supportive care, respectively. MRI imaging at 1-year post-treatment did not reveal any clinically meaningful safety findings.

In the control arm, mean CSF NfL remained stable or slightly declined (range, +1% to –35%) over 12 months. In treated patients, CSF NfL increased as expected following the surgical procedure (peak at 1-month post-treatment) and approached baseline at 12 months. Two treated participants were at or below baseline at 12 months post-treatment and 3 were at or below baseline at 15- and 18-months post-treatment. Altogether, treated participants had an 8% increase compared to baseline (range, +46 to -14).

Mean CSF mHTT declined from baseline in 4 evaluable treated patients with a 53.8% reduction from baseline at 12 months post-treatment (range, 44-71). Three evaluable control patients experienced a mean increase in CSF mHTT from base line at 1, 3, 6, and 9 months and then a 16.8% decrease from baseline at 12 months (range, 35-47).

 with 26 total patients, 16 of which are in the high-dose cohort. uniQure also plans to initiate a third cohort of up to 18 patients in the trial that will evaluate the use of alternative stereotactic navigation systems to simplify placement of catheters for AMT-130 infusions. Participants will receive the high 6x10

 vg dose. This cohort is planned to complete enrollment by the end of 2023. In an additional, open-label trial being conducted in Europe, all 6 patients in the low-dose cohort and 4 of 9 patients in the high-dose cohort have received AMT-130.

“We have made excellent progress in our clinical investigation of AMT-130 and now have a total of 36 patients enrolled across our two Phase I/II clinical studies in the U.S. and Europe,” Matt Kapusta, chief executive officer, uniQure, added to the statement. “Enrollment in the high-dose cohort of our open-label European study is well underway and is expected to be completed by the end of this year. We look forward to continued collaboration with the Huntington’s disease community to advance AMT-130 as a potential treatment for those living with Huntington’s disease.”

uniQure announces update on low-dose cohort in phase i/ii clinical trial of AMT-130 gene therapy for the treatment of Huntington’s disease. News release. uniQure. June 23, 2022. https://www.globenewswire.com/news-release/2022/06/23/2467860/0/en/uniQure-Announces-Update-on-Low-Dose-Cohort-in-Phase-I-II-Clinical-Trial-of-AMT-130-Gene-Therapy-for-the-Treatment-of-Huntington-s-Disease.html

NfL peaked 1-month post-treatment as expected and returned to near baseline at 12 months. 

Huntington Disease Gene Therapy Promotes Reduction in Mutant Huntington Protein, Neurofilament Light 

The cell and gene therapy sectors are growing exponentially, with new players emerging daily and much progress being made both in and out of the lab. 

Around the Helix is your chance to catch up with the latest news in cell and gene therapies, including partnerships, pipeline updates, and more.

1. IND Cleared for γδ T-Cell Therapy in Non-Hodgkin Lymphoma

The FDA has cleared the investigational new drug application (IND) for Acepodia’s ACE1831, a γδ T-cell therapy, for the potential treatment of non-Hodgkin lymphoma, which will soon be evaluated in a phase 1, first-in-human clinical trial.

2. Children Treated With Zolgensma for Presymptomatic SMA Achieve Age-Appropriate Motor Milestones

Novartis’ onasemnogene abeparvovec was shown to be both effective and well-tolerated for children expected to develop spinal muscular atrophy type 1 or type 2, according to findings from SPR1NT (NCT03505099), a phase 3 multicenter, single-arm trial.

3. Vutrisiran Approved for hATTR Amyloidosis

The FDA has approved Alnylam’s investigational subcutaneous RNA interface therapy vutrisiran, marketed as Amvuttra, for the treatment of transthyretin-mediated (ATTR) amyloidosis, based on positive 9-month results from the phase 3 HELIOS-A study (NCT03759379).

4. Collaboration to Focus on CAR T Therapy in Solid Tumors

MD Anderson Cancer Center, Invectys, and the Cell Therapy Manufacturing Center, which is a joint venture between MD Anderson and National Resilience, are collaborating to develop a scalable process for human leukocyte antigen-G targeted CAR T cell therapies for the potential treatment of solid tumors.

5. Akadeum Gets Patent for Cell-Sorting Technology

Akadeum Life Sciences has been granted a patent for their proprietary method of buoyancy-based cell sorting from biological fluid samples. Notably, the patent applies to the company’sT and B Cell isolation kits used in cell therapy manufacturing.

6. Partnership to Advance Gene-Editing Cell Therapy in Solid Tumors

Affini-T Therapeutics is combining their T-cell expertise with Metagenomi’s gene-editing technologies to create ex vivo T cell receptor therapies for solid tumors.

7. NorthX Biologics Opens Cell Therapy Manufacturing

The company will begin to manufacture cell therapies at their existing facilities as well as at the Karolinska University Hospital campus in Stockholm, Sweden. NorthX is also partnering with Alder Therapeutics, a cell therapy company.

8. OrganaBio Launches Cell Therapy Manufacturing

The company has launched contract operations at its new cell therapy manufacturing facility.

9. Invetech’s Korus to Improve Cell Elutriation

Korus is a closed system for autologous cell therapies that uses gentle counterflow centrifugation to improve elutriation and cell wash. So far, data indicate improved manufacturing performance compared to standard washing.

10. New Startup Immuneel Launches CAR T Trial

The startup has launched with $15 million and has started dosing patients in the phase 2 IMAGINE trial of ARI-0001 in patients with acute lymphoid leukemia. The trial is India's first CAR T-cell therapy trial.

The EMA has validated Bristol Myers Squibb’s type II variation application to extend lisocabtagene maraleucel’s indication to include patients with diffuse large B-cell lymphoma, high grade B-cell lymphoma, primary mediastinal large B-cell lymphoma and follicular lymphoma grade 3B, who are refractory or have relapsed within 12 months of initial therapy and are candidates for hematopoietic stem cell transplant.

12. Rochester and Sana Partner to Develop Neurologic Cell Therapies

The partnership builds on existing collaboration between University of Rochester Medical Center and Sana Biotechnology and will support the developmetn of cell therapies for possible indications including Huntington disease, Pelizaeus-Merzbacher disease, and secondary progressive multiple sclerosis.

13. Verismo and UPenn Enter Research Partnership

Verismo will fund additional research focused on the novel KIR-CAR platform for CAR T-cells to advance treatment options for solid tumors under a Sponsored Research Agreement.

14. Carbon Biosciences Launches With Cystic Fibrosis Gene Therapy Program

Carbon has launched with $38 million of funding, including $6 million from the Cystic Fibrosis Foundation. It’s lead program is CGT-001, a gene therapy for the potential treatment of cystic fibrosis developed with the company’s novel platform.

15. Novartis and Precision Bio Collaborate on Gene Editing

The partnership is targeting hemoglobinopathies such as sickle-cell disease and β-thalassemia. Therapies will be developed with Precision's ARCUS genome editing platform.

16. Kiromic Prioritizes γδ T-Cell Therapy

Kiromic Biopharma has shifted to prioritize its allogeneic, non-engineered off-the-shelfγδ T-cell therapy candidate, Deltacel (KB-GDT) for solid tumors. The company expects to submit an IND in the second half of 2022.

17. Lifespan Cancer Institute Gets Stem Cell Therapy Approval

The institute located at Rhode Island Hospital will now be able to treat patients with cancer with stem cell therapies.

18. Galapagos’ Acquisitions Expand Cell Therapy Operations

Galapagos NV is set to acquire CellPoint and AboundBio, giving the company access to new platforms and cell therapy models.

Catch up on the latest news, breakthroughs, and announcements from biotechnology companies making advancements in cell and gene therapies. 

Around the Helix: Cell and Gene Therapy Company Updates – June 22, 2022 

The adeno-associated virus vector (AAV) gene therapy BBM-H901 was well-tolerated and reduced the need for enzyme replacement therapy in patients with 

 as part of a phase 1 pilot trial (NCT04135300).

First author Feng Xue, MD, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China, and colleagues conducted the study to evaluate BBM-H901. The study was conducted at the Institute of Hematology & Blood Diseases Hospital. The gene therapy uses the engineered AAV843 capsid and expresses the Padua variant of factor IX (FIX).

“On the basis of preclinical studies, we launched a phase 1 trial on F9 gene transfer using BBM-H901. In contrast with all previous studies in this setting, a prophylactic glucocorticoid treatment 1 week before AAV vector infusion was explored to reduce the potential immune response against AAV capsid,” Xue and colleagues wrote.

Xue and colleagues enrolled 10 male participants in the study out of 12 screened between October 2019 and January 2021. Two were excluded due to hepatitis C infection. Participants had a mean age of 29.5 years (range, 20-59; standard deviation [SD], 11.0). Prior to enrollment, 6 participants on prophylactic therapy had a mean annualized bleeding rate (ABR) of 8.3 (SD, 3.5) and 4 participants using episodic treatment had an ABR of 41.3 (SD, 19.1

Dosing Continues in Hemophilia B Gene Therapy Trial

The 10 participants received a single intravenous dose of 5 × 10¹² vg/kg of BBM-H901 after 1 week of prophylactic 1 mg/kg oral prednisone. This dose continued for another week after infusion before tapering for a total course of around 8-10 weeks. Prednisone use was allowed to resume based on liver function for FIX activity during follow-up and participants were also allowed to receive FIX replacement therapy on demand or as prophylaxis after infusion.

Patients were followed up for safety analyses for 1 year after infusion and for a median of 58 weeks (IQR, 51.5-99.5) for activity analyses. The study was monitored by an independent safety monitoring committee. Investigators found that mean FIX activity reached 26.9 IU/dL (SD, 20.5) after follow-up. Overall, median ABR, which was 12 (IQR, 0.8-2.3) at baseline, fell to 0 after infusion (

= .0092). Similarly, median number of FIX concentrate infusions fell from 53.5 (IQR, 38-74) to 0 (

<.0001) after infusion. Median number of target joints for all participants also fell from 1·5 (IQR, 0.8-2.3) before infusion to 0 (

No participants experienced serious adverse events (AEs) of grade 3 or 4. Grade 1-2 AEs included pyrexia (n = 1; 10%) and aminotransferase elevations (n = 1; 10%). Two participants had alanine and aspartate aminotransferase elevations accompanied with decreases in FIX activity. No participants had FIX inhibitors and all developed AAV antibodies after infusion.

“Compared with other gene therapy trials for hemophilia B, faster expression of transgene was observed in this study... We believe that the rapid expression might be attributed to rapid delivery of gene into liver by the strong liver tropism of AAV843 capsid, because vector DNA in plasma was found to be rapidly cleared by at least three logs within 24 hours, indicating the rapid liver uptake and rapid uncoating of the AAV843 capsid in addition to the double-stranded AAV genome vector genome structure. Rapid uncoating might favor rapid degradation of the capsid protein within the cells, and possibly reduce the delayed T cell immune response against capsid protein-containing hepatocytes,” Xue and colleagues noted.

Investigators also performed exploratory single-cell RNA sequencing analyses that suggested that prophylactic glucocorticoid treatment reduced the baseline amounts of antigen-presenting cells, CD4+ T cells and CD8+ T cells, and upregulated Treg activation, showcasing a possibly useful regimen to blunt immune responses. This regimen is not yet validated and longer follow-up is also needed to confirm the long-term efficacy of BBM-H901.

Xue F, Li H, Wu X, et al. Safety and activity of an engineered, liver-tropic adeno-associated virus vector expressing a hyperactive Padua factor IX administered with prophylactic glucocorticoids in patients with haemophilia B: a single-centre, single-arm, phase 1, pilot trial. 

, 2022. Published online May 19, 2022. doi: 10.1016/ S2352-3026(22)00113-2

Annualized bleeding rate fell to 0 at a median of 58 weeks after infusion. 

Hemophilia B Gene Therapy Well-Tolerated, Reduced Need for FIX Replacement Therapy 

“It's like having a pipeline in a single product. So, we're able to take advantage of the biologic features of the cells, put them into multiple different indications, all with the same manufacturing processes. It's a fantastic opportunity for us because we can continue to mass produce these cells and continue to interrogate their capability across a host of different diseases.”

MiNK Therapeutics’ goal is to develop allogeneic invariant natural killer T (iNKT) cell therapies for oncologic and immune indications. iNKT cells combine the durability and memory of T-cells with the rapid killing power of NK cells.

MiNK’s lead program is AgenT-797, an off-the shelf iNKT cell therapy, in clinical trials in multiple myeloma (NCT04754100), solid tumor cancers (NCT05108623), and in patients with severe viral ARDS (NCT04582201). Initial data has demonstrated that the iNKT cell therapy has been well-tolerated when dosed up to 1 billion cells without lymphodepletion, with no incidences of cytokine release syndrome or neurotoxicity. Further data will be available in the second half of 2022.

spoke with Jennifer Buell, PhD, president and chief executive officer, MiNK Therapeutics, to learn more about the advantages of iNKT cells and the company’s CARDIS platform. She discussed data seen so far with AgenT-797.

MiNK Therapeutics announces patients dosed with AgenT-797 iNKT cell therapy in solid tumor cancers. News release. MiNK Therapeutics. March 3, 2022. https://investor.minktherapeutics.com/news-releases/news-release-details/mink-therapeutics-announces-patients-dosed-agent-797-inkt-cell

Jennifer Buell, PhD, president and chief executive officer, MiNK Therapeutics, discussed different indications for the iNKT therapy AgenT-797. 

Developing Invariant Natural Killer T Cells for Multiple Myeloma, GVHD

The FDA has cleared the investigational new drug application (IND) for 

 ACE1831, a γδ T-cell therapy, for the potential treatment of non-Hodgkin lymphoma (NHL).

"The FDA clearance of our IND application for ACE1831 is a significant milestone for Acepodia as we move into the clinic with a first antibody armed allogeneic gamma delta T cell product candidate through our unique Antibody-Cell Conjugation (ACC) platform. Based on ACE1831's encouraging preclinical data, we believe that our antibody ­armed gamma delta T cell therapy has the potential to provide additional treatment options for patients with NHL," Sonny Hsiao, PhD, chief executive officer, Acepodia, said in a statement.

 "The ACC approach allows us to circumvent the limitations of current T cell engager therapies. Meanwhile, we can also significantly reduce manufacturing costs and have the potential to generate a cost-effective cancer treatment for patients. We look forward to advancing ACE1831 into its first clinical trial," said the chief executive officer.

ACE1831 is an allogeneic, anti-CD20 γδ T-cell therapy developed with Acepodia’s ACC platform. The therapy will be evaluated in a phase 1, first-in-human, multi-center clinical trial in patients with NHL. γδT cells

Allogeneic CAR T-Cell Therapy Yields 100% CR Rate in B-NHL

“In an in vivo model, ACE1831 showed prolonged survival compared to treatment groups utilizing the same antibody and effector cells separately. In addition, ACE1831 is shown to trigger the release of interferon gamma but not interleukin-6 while engaging target tumor cells in vivo, suggesting that ACE1831 may activate the immune system without the risk of cytokine release syndrome,” Hsiao 

Acepodia’s lead program, ACE1702, is an allogeneic, amplified natural killer (NK) cell therapy also developed with the ACC platform.

 ACE1702 is currently being evaluated in a phase 1 trial (NCT04319757) in HER2-positive tumors. 

The study is primarily evaluating safety and tolerability via the incidence and severity of adverse events (AEs) and dose-limiting toxicities as well as the maximum tolerated dose and the phase 2 recommended dose. Secondary endpoints include pharmacokinetics and pharmacodynamics such as NK cell persistence and immune function. Other outcomes evaluate preliminary efficacy by measuring tumor response via RECIST 1.1, radiographic assessments, and serum tumor marker values.

“The trial will continue to enroll patients with advanced HER2-expressing tumors. Dose escalation is continuing up to 15 billion cells per cycle with updated clinical data to be provided in the first half of 2022,” Thorsten Graef, MD, PhD, chief medical officer, Acepodia, 

1. Acepodia announces FDA clearance of IND application for ACE1831, an anti-CD20 armed allogeneic gamma delta T-cell therapy candidate to treat patients with non-Hodgkin's lymphoma. News release. Acepodia. 

https://www.prnewswire.com/news-releases/acepodia-announces-fda-clearance-of-ind-application-for-ace1831-an-anti-cd20-armed-allogeneic-gamma-delta-t-cell-therapy-candidate-to-treat-patients-with-non-hodgkins-lymphoma-301570711.html


2. Acepodia Presents Positive Interim Phase 1 Feasibility Data for Antibody Cell Effector Therapy, ACE1702, in Advanced HER2-Positive Tumors. News release. Acepodia. September 16, 2021. https://www.globenewswire.com/news-release/2021/09/16/2298101/0/en/Acepodia-Presents-Positive-Interim-Phase-1-Feasibility-Data-for-Antibody-Cell-Effector-Therapy-ACE1702-in-Advanced-HER2-Positive-Tumors.html

ACE1831 will soon be evaluated in a phase 1, first-in-human, clinical trial. 

IND Cleared for γδ T-Cell Therapy in Non-Hodgkin Lymphoma 

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

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. 