“There used to be a paucity of industry interested in NK cell biology and now that's exploded. Now, everybody's interested in autologous NK cells or induced pluripotent stem cells-derived NK cells.”

Natural killer (NK) cell approaches are being investigated more and more for treating both hematologic malignancies and solid tumors. Presentations on new NK cell approaches were given at the 

European Society of Medical Oncology (ESMO) Congress 2022

, held September 9-13, in Paris, France. One such presentation was given by Jeffrey Miller, MD, professor and deputy director of the Masonic Cancer Center of the University of Minnesota, on GTB-5550, a B7H3 tri-specific killer engager (TriKE) that specifically stimulated expansion of natural killer (NK) cells in preclinical models of multiple cancers.

The novel dual camelid (cam) TriKE contains wild type interleukin-15 and 2 cam engagers that target CD16 on NK cells and B7H3 on multiple solid tumors. The data presented demonstrated GTB-5550'sability to increase activity of NK cells against cancer cells after stimulation.

 spoke with Miller to learn more about NK cell research and other promising approaches discussed at the ESMO Congress. He touched on new avenues of research including NK cell combinations with PD1 blockades and different platforms to produce NK cells.

Click here to read more coverage of ESMO Congress 2022.

Miler JS, Zorko N, Merino A, et al. B7H3-targeted tri-specific killer engagers deliver IL-15 to NK cells but not T-cells, and specifically target solid tumors as a pan-tumor antigen strategy mediated through NK cells. Presented at: ESMO Congress 2022, September 9-13, Paris, France.

Videos

The deputy director of the Masonic Cancer Center discussed trends of presentations from ESMO 2022. 

Jeffrey Miller, MD, on Emerging Research With Natural Killer Cells 

The first patient has been dosed in a phase 1/2 clinical trial (NCT05144386) of Excision BioTherapeutics’ EBT-101, an in vivo CRISPR-based gene editing approach intended for the treatment of 

 and dual guide RNAs via an adeno-associated virus (AAV), targeting 3 sites in the HIV genome for excision, with the intention of minimizing viral escape. According to Excision’s announcement, the first patient’s dosing occurred in July of this year and the therapy has been well-tolerated in the time since then. The patient is expected to qualify for analytical treatment interruption (ATI) of background anti-retroviral therapy (ART). EBT-101 previously demonstrated positive efficacy data in transgenic mice and positive long-term safety data in non-human primates.

“Dosing the first participant with EBT-101 is a landmark event that solidifies Excision’s position as a pioneer in gene editing,” Daniel Dornbusch, chief executive officer, Excision, said in a statement regarding the news. “It is the first time a CRISPR-based therapy targeting an infectious disease has been administered to a patient and is expected to enable the first ever clinical assessment of a multiplexed, in vivo gene editing approach. We were able to reach this watershed moment thanks to years of innovative work by leading scientists and physicians, to whom we are immensely grateful. With this achievement, Excision has taken a major step forward in developing a one-time treatment that could transform the HIV pandemic by freeing affected people from life-long disease management and the stigma of disease.”

The open-label, multicenter study is expected to enroll approximately 9 male patients aged 18 years to 60 years with documented chronic HIV-1 infection. Participants must be on a stable ART regimen for more than 2 years prior to screening and must have plasma HIV-1 RNA levels below the limit of quantification. Patients are additionally required to have a body weight between 45 and 90 kg (inclusive) and must be vaccinated for N. meningitidis and COVID-19. Patients who have had drug resistance to 2 or more classes of ART within the past 5 years, patients with more than 1 change in ART due to virologic failure in the past 2 years, and patients receiving long-acting injectable ART will be excluded from the study, as will patients with anti-AAV9 serum neutralizing antibodies greater than 1:20 titer. Patients with a history of HIV dementia or HIV-related cardiac disease, HIV-related kidney disease with abnormal renal function, or HIV-related opportunistic infections within the past 2 years will also be excluded. Additional exclusion criteria relate to past treatments and health status.

Participants will be divided among 3 cohorts and will receive a single dose of EBT-101 intravenously at 1 of 3 dose-levels, depending on their cohort. Twelve weeks after administration, eligibility for ATI will be assessed. The primary end point is the incidence and severity of adverse events. The trial will also evaluate biodistribution, pharmacodynamics, and efficacy. The study is taking place at multiple locations in the United States and is expected to be completed in March 2025. Participants will also be enrolled in a long-term follow-up study (NCT05143307), which will follow the patients for up to 15 years.

“There are nearly 40 million people worldwide suffering from the effects of HIV with no curative treatments available more than 40 years after its discovery,” Kamel Khalili, PhD, chair, Department of Microbiology, Immunology and Inflammation, director, Center for Neurovirology and Gene Editing, director, Comprehensive NeuroAIDS Center at the Lewis Katz School of Medicine at Temple University, co-founder, Excision, added to the statement. “We believe EBT-101 can address the long-standing unmet needs of people living with HIV by removing HIV DNA from their cells, thereby eradicating their infections. We believe we are well-positioned to collect key data that will enable our efforts to translate the success this approach has shown in animal models to human clinical trial participants. We look forward to investigating this hypothesis through the EBT-101 clinical program and are pleased that the EBT-101 phase 1/2 trial is proceeding as planned.”

Excision Biotherapeutics doses first participant in EBT-101 phase 1/2 trial evaluating EBT-101 as a potential cure for HIV. News release. Excision BioTherapeutics, Inc. September 15, 2022. 

https://www.globenewswire.com/news-release/2022/09/15/2516733/0/en/Excision-BioTherapeutics-Doses-First-Participant-in-EBT-101-Phase-1-2-Trial-Evaluating-EBT-101-as-a-Potential-Cure-for-HIV.html

Articles

The patient is expected to qualify for analytical treatment interruption of background anti-retroviral therapy.

HIV Gene Editing Clinical Trial Treats First Patient

 Weekly Rewind! We’ve compiled 5 highlights from this week’s coverage of advances in gene and cell therapies, including FDA actions, notable research, and interviews with experts across the field.

1. Eli-Cel Approved for CALD, Marking Second Gene Therapy Win for bluebird bio

The approval follows unanimous support of eli-cel's benefits in CALD from an FDA AdComm meeting and an approval for beti-cel in beta-thalassemia.

2. Roberto Giugliani, MD, PhD, on Reducing GAGs in MPS Type 2 With Gene Therapy

The professor of genetics at Federal University of Rio Grande do Sul discussed updated data from the CAMPSIITE trial.

3. Zevor-Cel Yields 100% ORR in R/R Multiple Myeloma

Eleven patients in the LUMMICAR-2 trial were evaluable for preliminary efficacy analyses.

4. David S. Hong, MD, on the SURPASS Clinical Trial and TCR T-cell Therapy in Solid Tumors

Hong presented data from the SURPASS clinical trial at the 2022 European Society for Medical Oncology (ESMO) Congress.

5. Intellia Nets Positive Data Across In Vivo CRISPR Therapies for ATTR Amyloidosis Cardiomyopathy, Angioedema

Administration of NTLA-2001 led to rapid and deep reductions in serum TTR by day 28.

Review top news and interview highlights from the week ending September 23, 2022. 

CGTLive’s Weekly Rewind – September 23, 2022 

Pfizer and Sangamo Therapeutics have reopened enrollment in the phase 3 AFFINE study (NCT04370054) of giroctocogene fitelparvovec for the potential 

treatment of moderately severe to severe hemophilia A

Enrollment will resume across trial sites this September and dosing is expected to resume in October, with all sites predicted to be active again by the end of 2022. The companies expect to report a pivotal data readout in the first half of 2024.

“Ensuring the safety of study participants is our first priority,” Pfizer wrote in a study update.

 in November 2021 after Pfizer and Sangamo had voluntarily paused screening and dosing of participants due to Factor VIII (FVIII) activity greater than 150% in some participants.

 One such participant has since experienced below-the-knee deep vein thrombosis. Participants were treated with anticoagulants and protocols were amended to mitigate thrombotic risk. The FDA 

 in May 2022, but Pfizer kept the study on hold while discussing amended protocols with the agency.

BioMarin to Investigate B-ALL Case in Val-Rox Gene Therapy Clinical Trial

“Pfizer was recently made aware of an event of below-the-knee deep vein thrombosis in 1 trial participant with elevated Factor VIII levels. This patient had a history of thrombotic events prior to participation in the study, which is a known risk factor for subsequent events and an exclusion criterion for participation in AFFINE,” Pfizer reported in the earnings statement.

 “The case was assessed to understand all potential contributing factors, including missed doses of investigator-prescribed direct oral anti-coagulants. The patient is reported to be doing well.”

The study has a target enrollment of 63 participants with moderately severe to severe hemophilia A who have been followed on routine prophylaxis with FVIII products in the lead-in study (NCT03587116). The study’s primary endpoint is efficacy as measured by annualized bleeding rate (ABR) over 12 months compared with ABR on FVIII replacement therapy during the lead-in study. Secondary outcome measures include FVIII activity levels, annualized infusion rate of exogenous FVIII activity, annualized FVIII consumption, joint health, patient-reported outcomes, quality-of-life measures, and adverse events (AEs) for up to 5 years after treatment.

Giroctocogene fitelparvovec uses the adeno-associated virus vector 6 (AAV6) to deliver complementary DNA for B domain deleted human FVIII. The therapy uses multi-factorial modifications to the liver-specific promoter module, FVIII transgene, synthetic polyadenylation signal, and vector backbone sequence to optimize liver-specific expression. The FDA has previously granted orphan drug, fast track, and regenerative medicine advanced therapy designations to the therapy while the EMA has granted orphan medicinal product designation to the therapy.

1. Pfizer and Sangamo Therapeutics announce phase 3 trial of investigational gene therapy for hemophilia A has re-opened recruitment. News release. Pfizer. September 23, 2022. 

https://www.pfizer.com/news/announcements/pfizer-and-sangamo-therapeutics-announce-phase-3-trial-investigational-gene


2. Pfizer giroctocogenefitelparvovec (hemophilia A gene therapy) AFFINE phase 3 study update. News release. Pfizer. November 5, 2021. 

https://www.ehc.eu/pfizer-hemophilia-a-clinical-program-update_november-5th-2021/


3. Pfizer reports first-quarter 2022 results. Earnings release. Pfizer. May 3, 2022. 

https://s28.q4cdn.com/781576035/files/doc_financials/2022/q1/Q1-2022-PFE-Earnings-Release.pdf

The FDA previously lifted its clinical hold of the AFFINE study in May 2022.  

Pfizer, Sangamo Reopen Phase 3 Study of Hemophilia A Gene Therapy

(IND) to the FDA for its gene therapy candidate DB-OTO for the intended treatment of profound congenital hearing loss due to an otoferlin deficiency in pediatric patients.

“This submission is an important milestone for the Decibel team as we continue advancing our gene therapy pipeline to address areas of unmet medical need. DB-OTO may potentially provide a new treatment option for children born with otoferlin deficiency, a leading cause of infant hearing loss, for which there are no approved pharmaceutical remedies,” Laurence Reid, PhD, chief executive officer, Decibel, said in a statement.

 “We look forward to initiating a phase 1/2 clinical trial of DB-OTO in pediatric patients in the first half of 2023, pending regulatory clearance.”

DB-OTO, an adeno-associated virus (AAV) dual vector gene therapy, is being developed by Decibel in collaboration with Regeneron Pharmaceuticals. It expresses the otoferlin transgene in hair cells using a proprietary, cell-selective promoter, and is designed to enable the ear to transmit sound and restore hearing. It received

 orphan drug and rare pediatric disease designations

Gene Therapy for OTOF-Mediated Hearing Loss Gets Green Light to Enter the Clinic

“We are pleased to receive these important designations from the FDA, which support our conviction that innovative treatments for congenital hearing loss are urgently needed,” Heather Wolff, vice president, clinical development operations, Decibel, said in a statement at that time.

Prior to that, Decibel presented preclinical data at the 24th Annual Meeting of the American Society of Gene & Cell Therapy in May 2021.

 The data demonstrated DB-OTO's pharmacological modulation of otoferlin expression and durable functional rescue in mice as measured by the Auditory Brainstem Response.

Investigators tested a surgical delivery approach in mice translatable into routine otolaryngological practice to restrict transgene expression and prevent dose-limiting toxicities. The approach uses slow AAV infusion through the round window membrane and vestibular fenestration to allow egress of displaced perilymph by the therapy. This approach will be assessed in a potential clinical trial.

“Of the 1 in 500 neonates who are born with hearing loss annually in the US, 50 to 200 are caused by Otoferlin deficiency. There are no approved therapies for Otoferlin deficiency; infants with biallelic OTOF mutations are currently managed with assistive devices,” first author Adam Palermo, PhD, vice president, molecular platform, Decibel, and colleagues wrote.

 “DB-OTO is a promising emerging therapeutic for genetic hearing loss and has the potential to provide the first clinical proof-of-concept for gene therapy in the inner ear."

REFERENCES
1. Decibel Therapeutics announces submission of investigational new drug (IND) application for lead gene therapy candidate DB-OTO. News release. Decibel Therapeutics. September 20, 2022. 

https://www.globenewswire.com/news-release/2022/09/20/2519051/0/en/Decibel-Therapeutics-Announces-Submission-of-Investigational-New-Drug-IND-Application-for-Lead-Gene-Therapy-Candidate-DB-OTO.html


2. Decibel Therapeutics receives orphan drug and rare pediatric disease designations for DB-OTO for the treatment of otoferlin-related congenital hearing loss. News release. Decibel Therapeutics. September 9, 2021. https://www.globenewswire.com/news-release/2021/09/09/2294193/0/en/Decibel-Therapeutics-Receives-Orphan-Drug-and-Rare-Pediatric-Disease-Designations-for-DB-OTO-for-the-Treatment-of-Otoferlin-Related-Congenital-Hearing-Loss.html
3. Palermo A, Zhang X, Senapati A, et al. Development of an AAV-based gene therapy for children with congenital hearing loss due to otoferlin deficiency (DB-OTO). Presented at 2021 American Society of Gene & Cell Therapy; May 12-15. Abstract 579.

The company previously presented positive preclinical data at the 2021 ASGCT meeting. 

Decibel Puts Forth Congenital Hearing Loss Gene Therapy for Clinical Trials 

“The results are quite interesting. The lower dose and the normal doses were able to significantly decrease the levels of the glycosaminoglycans in the central nervous system... We saw a very significant reduction of this just a few weeks after infusion. With the higher dose, the results are still more significant, we were able to see over 80% reductions in some cases.”

RGX-121, REGENXBIO’s gene therapy intended for the treatment of mucopolysaccharidosis type 2 (MPS II; Hunter syndrome) was well-tolerated with promising efficacy, according to updated data from the phase 1/2/3 CAMPSIITE trial (NCT03566043).

These data were presented by Roberto Giugliani, MD, PhD, professor, genetics, Federal University of Rio Grande do Sul and chief, medical genetics service,Clinic Hospital of Porto Alegre, Rio Grande do Sul, Brazil, at the Society for the Study of Inborn Errors of Metabolism (SSIEM) 2022 Annual Symposium, in Freiburg, Germany, taking place August 30 – September 2, 2022.

 discussed the updated data from CAMPSIITE with Giugliani. He highlighted the significant reductions in glycosaminoglycans in the cerebral spinal fluid seen in the trial and the positive safety profile of the intra cisternal magna administration of the therapy.

Giugliani R. RGX-121 gene therapy for the treatment of severe mucopolysaccharidosis type II (MPS II): Interim analysis of data from a phase 1/2 study. Presented at: SSIEM 2022 Annual Symposium, Freiburg, Germany, August 30 – September 2, 2022.

The professor of genetics at Federal University of Rio Grande do Sul discussed updated data from the CAMPSIITE trial. 