by Manasi Vaidya in New York.
Fate TherapeuticsandCelyadsnatural killer (NK) cell biology-focused cell therapies could overcome cell persistence challenges and consequent efficacy concerns with redosing strategies, experts said.
One of Fate Therapeutics lead products, FT596, is an allogeneic, multitargeted, chimeric antigen receptor (CAR) NK cell product. Celyads autologous CYAD-01 and CYAD-02 and allogeneic CYAD-101 are CAR T cell products using NK cell specificity to target T-cells. One analyst considered the potential to redose allogeneic products as a key item to consider while assessing clinical potential. While clinical data establishing the additive efficacy advantages of giving multiple doses is still preliminary, redosing allogeneic products could increase their expansion and persistence, experts said. Autologous therapies carry source constraints, so the ability to manufacture and administer allogeneic therapies is an advantage, they said.
While past NK cell therapy data has been mixed, experts saw potential in CAR NKs like FT596 or CAR T-cell products engineered to express NKG2D like CYAD-101, given the advancements in cell production.
Phase I FT596 results in B-cell lymphomas/ CLL are expected at either the American Society of Hematology (ASH) meeting in December or an investor meeting in early 2021, as per a second analyst report. Phase I data for CYAD-01 and CYAD-02 in relapsed/refractory (r/r) acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) are expected by YE20, as per the companys August corporate presentation. Celyads allogeneic CYAD-101 is being tested in a Phase I alloSHRINK trial (NCT03692429) in metastatic colorectal cancer (CRC), which has a primary completion date of November 2020.
FT596s sales are expected to reach $136m in 2026, according to a GlobalData Consensus forecast. Celyad did not respond to a request for comment.
Increasing the persistence of cell therapies once they are infused into a patient has been a challenge, especially with NK cell-based therapies, experts said. The issue of persistence and consequent efficacy is significant because the potential efficacy with Celyad and Fate Therapeutics platforms remains largely unknown, they added.
Because the immune system can recognise foreign cells, cell products would not last for more than a few weeks, said Dr Marco Davila, medical oncologist, in the Department of Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, Florida. With CAR T-cell therapies, the expansion and persistence of CAR cells are said to correlate with the durability of response, said Dr David Sallman, assistant member, Department of Malignant Hematology, Moffitt Cancer Center.
Strategies involving multiple doses of cell therapies could maximise the total dose, improve duration, and increase efficacy magnitude with both autologous and allogeneic cell therapies, said Dr Tara Lin, associate professor of medicine, University of Kansas Medical Center, Kansas City. Multiple infusions of therapy could also potentially lead to complete remission, said Sallman. In Fate Therapeutics Phase I FT500 (NCT03841110) study, patients had been given up to six doses of the therapy, which was not found to be toxic, according to Fate Therapeutics CEO Scott Wolchko. Redosing has the potential to offer multiple infusions as maintenance therapy, said Dr Jeffrey Miller, professor of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis.
The persistence of allogeneic therapies is not well understood, and it is unknown how long cells need to persist to be effective or whether persisting cells confer durability of response, said Wolchko. Giving multiple doses is one way to overcome the lack of persistence if it is an important factor for efficacy, he said. In a 4Q19 call, the FDA said it was allowing the dose to be repeated on a patient-by-patient basis, Wolchko said. In the alloSHRINK study, CYAD-101 is administered three times with a two-week interval between each administration in metastatic CRC, as per ClinicalTrials.gov.
However, even if the engineered cells do not persist in the body, the response rate and ability to eradicate the disease should not be limited, said Davila. With a limited lifespan, allogeneic cell therapies would dissipate as the patients immune system recovers, said Dan Kaufman. With the incorporation of interleukin (IL)-12 or IL-15 into the cell product, the cell therapy could persist without exogenous cytokines, said Kaufman. The FT596 construct contains an IL-15 fusion protein.
Experts cited the data from a Phase I / II (NCT03056339) investigator-led effort at MD Anderson Cancer Center using cord blood-derived anti-CD19 CAR NK cells as an example of an effective CAR NK therapy. The study by Rezvani and colleagues showed a persistence challenge did not seem to hamper the response, because once a critical threshold for cell expansion is crossed, the activity can be mediated, Davila said. Eleven r/r patients with CD19-positive cancers, such as non-Hodgkins lymphoma or CLL, were treated with a single infusion; eight had a response, including seven with a complete remission (Rezvani et al.  N Engl J Med, 382, pp. 545553). Even if the cells do not persist, they expand to sufficient levels to eradicate the disease before they are lost, Davila added.
In the Phase I THINK(NCT03018405) CYAD-01 data, decreased bone marrow blasts were observed in eight patients, including five objective responses and one stable disease for three or more months, as per the company presentation. Responding patients did have blast clearances, but some of the remissions were short-lived and the cells did not persist in the system, said Sallman. However, the short hairpin (sh) ribonucleic acid (RNA) technology employed CYAD-02, which could increase persistence and expansion, said Sallman (Fontaine et al., Blood, 134[Suppl 1], p. 3931). ShRNA technology allows T cell engineering without the need for gene editing to inhibit alloreactivity and increase persistence, according to Celyad.
Ongoing research on improving preconditioning regimens by combining additional drugs could also help with the persistence of allogeneic products, said Davila. It is not known whether every dose needs a conditioning regimen, but since conditioning regimens can suppress a patients immune system for several months, it may not be necessary before every therapy infusion, he added.
Patients will not have to receive a preconditioning regimen before every cell infusion, said Wolchko, adding redosing FT500 was found to be safe. Celyads protocol does not specify the preconditioning strategy for redosing. No predictive biomarkers are available to explain why some patients respond well and others do not, said Sallman, adding it is critical to identify potential responders. Nonetheless, there is no way to predict clinical efficacy based only on preclinical data, so data is still needed, said Miller.
The economic advantage to developing off-the-shelf therapies has driven interest in NK-cell based platforms, said Miller and Davila. If quick treatment is needed, then an allogeneic NK cell therapy would be better than an autologous therapy, which may take up to six weeks to manufacture, said Sallman. While the results with autologous CAR T-cell therapies have been significant, their scale-up and costs are challenging, said Kaufman.
Latest report from Visit GlobalData Store
The ability to use induced pluripotent stem cell (iPSCs) or cord blood cells as a source would help scale up the cell manufacture and allow effective results, said Kaufman. iPSCs provide advancement in expansion protocols, which can provide multiple doses, Miller added. Fate Therapeutics has an iPSC-derived NK cell franchise. Also, since T cell therapies require donor apheresis to collect cells in a process lasting four to five hours, it is not feasible to keep going back to the same donor, said Miller.
Moreover, newer platforms are expected to improve on past NK cell therapy trials, specifically those showing mixed efficacy. Past studies had feasibility limitations in getting the required number of cells, said Miller. Those small studies were conducted at a time when cell isolation and production systems were not as advanced as they are now, said Davila.
Manasi Vaidya is a Senior Reporter for Clinical Trials Arena parent company GlobalDatas investigative journalism team. A version of this article originally appeared on the Insights module of GlobalDatas Pharmaceutical Intelligence Center. To access more articles like this, visit GlobalData.
Latest report from Visit GlobalData Store
Gas Particle Analysis Devices for Medical and Food Sectors
Lines and Machines for Pharmaceutical Solids Production
Tamper-Evident Solutions for Pharmaceutical Packaging
- Study Finds Racial and Ethnic Disparities in Treatment of AL Amyloidosis - DocWire News - November 22nd, 2020
- New Virtual Reality Tool, Domestic Cats are SARS-CoV-2 Carriers, Combination Therapy Advances: COVID-19 Updates - Bio-IT World - November 22nd, 2020
- SEE | Smoking worsens Covid-19 infection in the airways, new study reveals - Health24 - November 22nd, 2020
- Could Cell Therapy Be The Answer To COVID-19? - CBS Boston - November 3rd, 2020
- CA Prop 14 Explained: What To Know Before You Vote Election Day - Los Angeles, CA Patch - November 3rd, 2020
- GMP Cell Banking Services Market Predicted to Accelerate the Growth by 2019-2029 - TechnoWeekly - November 3rd, 2020
- Making Progress Against Relapsed/ Refractory DLBCL Without CAR T - OncLive - November 3rd, 2020
- Orchard Therapeutics to Host Virtual R&D Investor Event on Friday, November 13, 2020 - GlobeNewswire - November 3rd, 2020
- Editorial Article: Combating cancer: The incubation technology accelerating CAR-T cell therapy development - SelectScience - October 31st, 2020
- Richters Transformation: When a Slow-Growing Cancer Turns Aggressive - SurvivorNet - October 31st, 2020
- Detroit Pistons, Make-A-Wish put a smile on the face of Commerce Township boy - The Oakland Press - October 31st, 2020
- NexImmune Establishes Research Initiative with City of Hope to Focus on Novel Immunotherapeutic Approaches to Acute Myeloid Leukemia - Yahoo Finance - October 31st, 2020
- HBS and Harvard's Department of Stem Cell and Regenerative Biology Receive $25 Million Gift from The Chris and Carrie Shumway Foundation to Support... - October 23rd, 2020
- Harnessing regeneration of retinal tissues: An option almost within reach - Ophthalmology Times - October 23rd, 2020
- World Wide Stem Cell Treatment Centers Provides Exceptional Regenerative Treatment Options To Those in Need - GlobeNewswire - October 16th, 2020
- Proposition 14: Stem cell research bonds City Times - City Times - October 16th, 2020
- BrainStorm Announces Financial Results for the Third Quarter of 2020 and Provides a Corporate Update - PRNewswire - October 16th, 2020
- How a UCSF team is giving Cronutt the sea lion a second chance with neuroscience - University of California - October 16th, 2020
- Caliber Pain is Featured as a 2020 Top NYC Patient Rated Pain Management Practice by Find Local Doctors - PR Web - October 10th, 2020
- Report of the president: Appointments and promotions | Stanford News - Stanford University News - October 10th, 2020
- UTSW Scientist: 'We Need More Women Thinking Creatively in the Lab and Pushing Science Forward' - dallasinnovates.com - October 10th, 2020
- Here's what is known about Trump's COVID-19 treatment - Science Magazine - October 4th, 2020
- Election Guide: Here's What You Need to Know About Proposition 14 - NBC Bay Area - October 4th, 2020
- ASX up 2.3%, banks and energy outperform - The Sydney Morning Herald - October 4th, 2020
- Autologous Stem Cell and Non-Stem Cell Based Therapies MARKET 2020 |INDUSTRY ANALYSIS, SIZE, SHARE, TRENDS, MARKET DEMAND, GROWTH, OPPORTUNITIES AND... - September 25th, 2020
- Finding The Achilles Heel of A Killer Parasite - Newswise - September 25th, 2020
- SHE Initiative Shines Light on Gender Disparities in Oncology Workforce - Targeted Oncology - September 25th, 2020
- Actinium Pharmaceuticals Successfully Completes First Dosing Cohort in the Phase 1 Study of Actimab-A and Venetoclax Combination Therapy in... - September 23rd, 2020
- Advances in the Treatment of Mantle Cell Lymphoma are Greatly Improving the Long-Term Outlook for Patients - Curetoday.com - September 23rd, 2020
- CytoDyn's Phase 2 Study of Leronlimab for Mild-to-Moderate COVID-19 Selected for Oral Presentation at the Special isirv-AVG Virtual Conference on... - September 23rd, 2020
- Opdivo (nivolumab) Demonstrated Superior Disease-Free Survival in Patients with Resected Esophageal or Gastroesophageal Junction Cancer Compared to... - September 23rd, 2020
- Coronavirus Researchers Discover How COVID-19 May Trigger Fatal Levels of Lung Inflammation - SciTechDaily - September 21st, 2020
- The Holistic Sanctuary Announces Exciting Plans to Expand Over Next 4 Years and Save More Lives - PRNewswire - September 21st, 2020
- Robert E. Windsor, MD, is being recognized by Continental Who's Who - PRNewswire - September 21st, 2020
- City of Hope Enters Licensing Agreement With Chimeric to Develop Its Pioneering Chlorotoxin CAR T Cell Therapy - Business Wire - September 21st, 2020
- Emerging immunotherapies in multiple myeloma - The BMJ - September 21st, 2020
- ADC Therapeutics Submits Biologics License Application to the U.S. Food and Drug Administration for Loncastuximab Tesirine for Treatment of Relapsed... - September 21st, 2020
- Oakland 24-year-old seeking multiethnic bone marrow donor - The Jewish News of Northern California - September 21st, 2020
- First-Line Treatment With Merck's KEYTRUDA (pembrolizumab) Doubled Five-Year Survival Rate (31.9%) Versus Chemotherapy (16.3%) in Certain Patients... - September 21st, 2020
- Coronavirus, Charity, and the Trolley Problem - Crooked - September 12th, 2020
- Targeted Approach Considered for the Treatment of Accelerated/Blast Phase MPNs - Targeted Oncology - September 1st, 2020
- Royal Biologics Announces the Acquisition of FIBRINET - PRNewswire - September 1st, 2020
- Novel Targets Outside of JAK Inhibition Inching into Myelofibrosis Treatment Landscape - Targeted Oncology - September 1st, 2020
- MaaT Pharma to Announce Clinical Data with its Lead Microbiota Biotherapeutic in Intestinal Acute GvHD at Virtual 46th Annual Meeting of the European... - August 28th, 2020
- The Inside Story Of Biotechs Barnum And His Covid Cures - Forbes - August 28th, 2020
- Mustang Bio: Slow, Steady Progress Towards Multiple Gene And CAR-T Therapy Goals - Seeking Alpha - August 25th, 2020
- Study sheds light on why retinal ganglion cells are vulnerable to glaucoma - Jill Lopez - August 19th, 2020
- Coronavirus Thursday update: UMN announces new stem cell treatment - TwinCities.com-Pioneer Press - August 15th, 2020
- Health and Fitness: Hip replacement surgery: getting back to what you love - taosnews - August 14th, 2020
- How MC Hammer And Other Performing Artists Are Sharing Their Love Of Science - Forbes - August 12th, 2020
- Chromosomal Rearrangements Associated with Chemotherapeutic Drug Resistance | McDonnell Boehnen Hulbert & Berghoff LLP - JD Supra - August 8th, 2020
- Chinese Govt-Compensated Experts Plead Guilty to Thieving Investigation From an American Childrens Medi ... - 90Xtra - August 7th, 2020
- US government considers ethics of aborted tissue research - Angelus News - August 7th, 2020
- Mesa Discusses Treating Myelofibrosis and Other MPNs - Targeted Oncology - August 7th, 2020
- Startup Accelerator: Volumetric Aims to Be the Tissue Bioprinting Farm of the Future - 3DPrint.com - August 6th, 2020
- Cord blood offers hope for rare diseases and ethnic minorities - The Province - August 6th, 2020
- FDA touts advanced manufacturing to address Covid-19 shortfalls - Endpoints News - August 5th, 2020
- Cancer Research Institute Awards $30.2 Million in Grants and Fellowships to Support Basic and Clinical Research in Immunology and Cancer Immunotherapy... - August 5th, 2020
- RenovaCare Appoints Dr. Lydia M. Evans to Its Board of Directors and Increases Board Membership - GlobeNewswire - August 4th, 2020
- MediVet Biologics Rebrands as Ardent Animal Health - Benzinga - August 3rd, 2020
- Church Point Police Captain dies from COVID-19 complications: 'Go and protect the heavens, my dearest friend' - The Advocate - August 1st, 2020
- BMT survivor study finds significant breast cancer risk in young women who received total body irradiation - The Mix - July 31st, 2020
- Hyperbaric Oxygen Therapy Can Enhance Cognition in Healthy Older Adults - PsychCentral.com - July 29th, 2020
- The surprising recovery with stem cells of 26 COVID-19 patient in Hidalgo - Explica - July 29th, 2020
- Johnny Tabaie is proud to announce the most powerful Stem Cell Therapy - Press Release - Digital Journal - July 29th, 2020
- COVID-19 Fibroblast Based Cell Therapy Candidate Shown to Reduce Lung Scarring in Aggressive Animal Model - El Paso Inc. - July 25th, 2020
- 'Self-eating' process of stem cells may be the key to new regenerative therapies - 7thSpace Interactive - July 23rd, 2020
- R3 International Now Including Exosomes with Stem Cell Therapy Program for Autism in Mexico - PR Web - July 23rd, 2020
- CAR T-Cell Therapy Offers Potential Solution for Relapse in MCL, But With Toxicity Risk - Targeted Oncology - July 22nd, 2020
- Fine-tuning adoptive cell therapy for advanced cancers - Newswise - July 22nd, 2020
- Global Cart Cell Therapy Market To Grow At A CAGR of 29.4% With The Emergence Of Immunotherapies In Medical Treatment - GlobeNewswire - July 22nd, 2020
- In Remission for 10 Years: Long-term Data on CAR-T Therapy - Medscape - July 21st, 2020
- MRFR predicts an Upsurge in the Leukemia Therapeutics Market valuation to USD 10.7 billion by 2023 - Jewish Life News - July 21st, 2020
- Cannabis Found Effective to Treat Sickle Cell Disease Pain - The Weed Blog - July 20th, 2020
- End of Palestinian Authority coordination with Israel in response to annexation threat: decision already impacting medical referrals - occupied... - July 20th, 2020
- Addiction Treatment Market Survey Report 2020 Stats and Forecasts to 2026 - Cole of Duty - July 18th, 2020
- 13 Promising Covid Treatments Emerging from Israel - The Jewish Voice - July 15th, 2020
- New Clues from Fruit Flies about the Critical Role of Sex Hormones in Stem Cell Control - Newswise - July 15th, 2020
- Impact of Covid-19 on Preimplantation Genetic Testing Market is Projected to Grow Massively in Near Future - Cole of Duty - July 13th, 2020
- Covid-19 Update : Cord Stem Cell Banking Market 2020 Outlook and Deep Study of Top Key Players Cryo-Save AG, Lifecell, StemCyte India Therapeutics... - July 13th, 2020