What started out as a journey to better understand regulatory T cells has now led to an intriguing approach with an investigational cell therapy designed to prevent the risk of graft-versus-host disease (GVHD) and to improve relapse-free survival rates in patients undergoing hematopoietic stem cell transplantation (HSCT).
Data of a phase 1/2 trial recently showed that the first-generation precision cell treatment Orca-T compared with a historical control of standard HSCT demonstrated faster neutrophil (median, 12 days vs 14 days; P < .0001) and platelet engraftment (median, 11 days vs 17 days; P < .0001), decreased incidence of grade 2 or higher GVHD at 100 days (10% vs 30%, P = .005) and chronic GVHD at 1 year (3% vs 46%, P = .0002).1,2
The 1-year GVHD-free and GVHD relapse-free survival (GRFS) rates were 75% with the use of Orca-T vs 31% with standard HSCT (P < .0001). The comparator cohort was derived from contemporaneous patients who had been treated at Stanford University with a conventional allograft.
Along with feasibility of the approach, the results also highlight how Orca-T demonstrates potent anti-leukemic activity in patients who have active disease at HSCT, which suggests that the decrease of GVHD does not impact graft-vs-leukemia (GvL).
That is the most exciting part about the Orca-T story; it is the ability to do this with precision, with speed, and to export it to other sites. The results are intriguing, and very supportive, said Robert Negrin, a professor of medicine (blood and marrow transplantation), and chief of the Division of Blood and Marrow Transplantation at Stanford University.
In an interview with OncLive, Negrin, who is senior author on the trial, shared the evolution of Orca-T as a novel approach to HSCT, highlighted his robust experience with using this cell therapy at Stanford University, and how Orca-T is a potential prevention method for GVHD.
OncLive: Please provide some background to this therapeutic approach. What is the mechanism of action? How is it effective in patients undergoing transplant?
Negrin: This whole idea came from mouse studies many, many years ago, where we identified GVHD as being a dysregulated immune reaction that just keeps going, and going, and going. Like you and I, when we react to something, we have a reactionlet's say, influenza. Our body responds, and then we stop reacting and you get better. With GVHD, what we noticed in using a bioluminescent animal model is that the alloreactive T cells just keep going, going, and going and are unrelenting in mice, just like in people. The problem is very similar and affects certain organs in a very similar way.
Therefore, we went about trying to understand the use of so-called regulatory cells. These are cells that everybody has that help control immune reactions. We just applied them in this clinical scenario, first in mice work done by Matthias Edinger, MD, when he was a postdoctoral fellow many years ago [and other researchers]. All of them were very actively involved in these studies, and showed, somewhat surprisingly, that the administration of regulatory T cells could control this dysregulated immune response that we called GVHD.
Probably more surprising was that, at least in the animal models, it also allowed for the benefits of transplant, namely, the graft-vs-tumor effect and better immune recovery. This was in large part because GVHD also impacts the immune repertoire and where the immunity is developed in the recipient.
All of this was very nice in mouse models and was very elegant. We did a lot of studies, published a number of nice papers, and thought this would be a great idea because it sort of solved, or at least addressed, the principal problems after bone marrow transplantationnamely, avoidance of GVHD yet retention of graft-versus-tumor effects and better immunity. A lot of times, people say, "Oh, that sounds good in mice, but, that's too good to be true." And, theyll ask, "Will that all work in people?"
Where did the biggest challenges lie in this approach?
The big challenge came about to try to apply this to patients. We also have one other interesting point that is relevant. If we gave the regulatory T cells first, before the so-called conventional CD4+/CD8+ cells, that allowed for a lower dose of regulatory T cells. This is because a big challenge is the paucity of these cells; you and I don't have that many.
Then, the other big challenge was the technical ability to isolate in cells. What we do in mice is cell sorting, which is a standard technology. But, that was not developed in people because we're bigthere are a lot of cells, and cell sorting is rather slow, and it's very specific. To get enough cells takes a really long time. It's somewhat of a heroic thing to do in people, to get the adequate amount ourselves; of course, we don't really know what this proper cell dose is.
However, what we thought we learned was that the ratio of conventional to regulatory T cells was the key component. Also, if you give the regulatory T cells first, you can get fewer numbers. Those are things you can do in transplant. You can get the cell from the donor, and you can give cells in a certain sequence; all of those things are very doable. It seemed like an attractive thing to do in patients.
Then, the question was: Does it work? There are 3 groups that have really pioneered this work. The first study came from the University of Perugia in Italy. They did this in haploidentical transplantation; you cannot avoid immunosuppression in haploidentical transplants. They were able to show in several nice papers that you could do this strategy, and seemingly, get away with low risk of GVHD, and also low relapse. This is because the other issue is: how do you measure the graft-vs-tumor effect? There is no assay, and we have no test; you have to wait and see who relapses and who doesn't. Therefore, they also showed rather convincingly that you could reduce GVHD risk, yet, there was a very low risk of relapse in their high-risk patient population. Those were very important [data].
Another study from the University of Minnesota did this with umbilical cord blood. They expanded the regulatory T cells from a third cord blood unit, which is somewhat heroicit is another level of complexity to isolate the cells and then expand them. We did this in matched donorseither matched siblings or matched unrelated donors. We published a paper in JCI Insight several years ago showing the initial results, and they look quite favorable.
Therefore, what I think is most exciting about what Orca Bio has done is they are developing technology to isolate the cells more quickly, to be able to do this on a clinical scale, with precision, and with speed. Also, [they are developing the technology] to be able to distribute it to anybody, because the criticism of all these studies is that, "Oh, that's nice. But, this is a single-institution study. Is this really true? Can this be exported? Could this be something that [an organization] other than these [individual] centers are really focused in this area and have developed these technologies could really do? Orca Bio is developing the technology, and improving the technology, because it's still very cumbersome, and exporting the technology so that you could do this, theoretically, at any center.
That's what I think is most exciting about the Orca Bio abstract; it is demonstrating that this can be done. It certainly opens the door to prevention of GVHD. As we move into an era of using cell-based therapeutics, now, this opens up many other possibilities, because you use these regulatory cells and autoimmune disorders and organ transplant tolerance. There are many other cell types that have potential clinical utility, but getting them, and purifying them, is a big challenge. There are many other possibilities that one could think of.
Obviously, more time will be required to follow these patients, but they certainly are supportive of the idea that you can improve overall outcomes using this strategy. That's what we hope to be able to demonstrate further.
Please focus on the scalability of this approach. Through these types of collaborations, how do you see Orca-T potentially moving through the FDA pipeline?
In academia, we don't develop drugs. It's too much, we don't have the resources, we don't have the capability, and we don't have the monitoring capability that is required for multi-institutional studies. Where these commercial partners come in is, they can raise money for interesting concepts, which Orca Bio has done, and they can export this to other centers, and that's critically important.
As we've seen in the CAR T-cell [therapy] world, that can be a quite successful commercial business. Also going through the process of an FDA approvalwhich Orca Bio is moving along in that processand getting the right designations is critically important to commercial entities. In academia, it's important to us, but that's just not our focus.
We don't have the resources around, the people and the expertise to really drive things through that process. We're good at developing the studies and getting FDA approvals, and [investigational new drug applications], but not really [good at] developing drugs as a commercial entity. This collaboration is key to doing this successfully; for example, at Orca Bio, [they have] technology to separate cells more efficiently and effectively. They also have the resources to do a multi-institutional clinical trial, and the expertise to move something through and present it to the FDA. Those are key components.
Could you expand on the study and respective data from this phase 1/2 trial?
Here at Stanford Cancer Institute, we did find in our patients that giving low doses of immunosuppressive medications with a single agent seem to improve the outcomes, and it's remarkable how well these patients have gone through the transplant. It's a little bit hard to appreciate an abstract until you take care of these patients, and many of them just sort of move to the transplant with relatively little challenges. We have not seen greater risks of things like infection [or] disease recurrence; those are obviously things that will be followed.
When we look at the 1-year GVHD relapse-free survival rate, which is an endpoint that most transplant studies would agree is the most important end point, the overall outcomes are much more favorable compared with a historical control group.
The data are very encouraging, and the overall outcomes look very strong in a reasonable number of patients now. We think it's important for the community to hear about it, and to get it on everybody's radar, and be excited about trying to move this forward as a more standard therapy. This is still a clinical trial, so it's not, it's not part of any standard therapies yet. We are using this quite regularly and have been very encouraged by the ease of which patients go through the transplant. It's still an allogeneic transplant; there still are many challenges there. However, these patients seem to be doing quite well, we're very encouraged, and so we keep going.
How does this approach impact patient outcomes as it relates to quality of life (QoL)?
The hard end points of 1-year relapse-free survival is obviously the most important to patients. However, going through an allogeneic transplant is obviously an incredibly difficult thing. Fortunately, I've only seen it [from] the doctor side, not [as a] patient.
However, I've seen many, many patients, and the quality of their life as they go through this experience is very important to all of us. As we saw these patients go through these studies, we felt like we were capturing something that was really important, and that is the ease [at which] many patients went through this experience, which just seemed different. It's hard to capture that.
It's really important for patients to speak and, and the way patients speak is in different ways. One way is through the QoL measures that they answer. This is [what they find] important, this is what they experiencednot what we say is happening. That's really important to hear that voice too. Those are data we're trying to collect. It's not so easy, because going through a bone marrow transplant is a poor QoL for everybody. But, by just to trying to capture this, [Orca-T seems] better than what we what we thought.
How has this changed the mindset of cell-based approaches in the community?
What has changed is the belief in the concept of cell-based therapies. A lot of these things are somewhat fanciful. It is also important to show that we can translate from an animal model [to a human]. There is a lot of criticism of animal modeling, because people say, "Well, it's nice for animal models, but it doesn't really translate into the clinic." Actually, my view is that because we don't actually follow the animal models, there are many compromises one needs to make. When you translate studies from animals to humans, there are many differences, and it's really important to try to follow them as carefully as you can within the limitations of what is possible. We were very engaged in that and tried to follow as carefully as we could. To me, that is very encouragingthat you can study things in animals that generate new concepts and be able to translate that into a clinical trial.
Obviously, with all of the caveats of an early-phase clinical trial, more time needs to pass, more patients to be treated, and you need to export [the treatment] to other centers. That's a really important point, because there are many things that get lost because, "it's too complicated. It's too expensive. People can't do it." I don't think anybody can do high-speed cell sorting, as a clinical project in a standard or standard cell-processing laboratory. It's above the level of what most processing laboratories can do.
- Asia-Pacific Cell Therapy Market 2021-2028 - Opportunities in the Approval of Kymriah and Yescarta - PRNewswire - August 5th, 2021
- Fate Therapeutics Announces Treatment of First Patient in Landmark Phase 1 Clinical Trial of ... - The Bakersfield Californian - August 5th, 2021
- IDH1 Inhibitors, CAR T-Cell Therapy, and Third-Generation TKIs Refresh Relapsed/Refractory Leukemia Landscape - OncLive - August 5th, 2021
- Lenzilumab Treatment May Provide Enhanced Likelihood of Survival Without Ventilation in Hospitalized Black and African-American COVID-19 Patients -... - August 5th, 2021
- Is This Small-Cap Biotech a Buy After Its Second Approved Gene Therapy? - Motley Fool - August 5th, 2021
- Defining Cell Culture Lines and Media - The Scientist - August 5th, 2021
- Preimplantation Genetic Testing Demand to Grow by 9% CAGR Annually, through 2031 - BioSpace - August 5th, 2021
- Cell Therapy Global Market Report 2021: COVID-19 Growth and Change to 2030 - ResearchAndMarkets.com - Business Wire - July 7th, 2021
- A New Era For FDA Regulation Of Cell And Tissue Products - Law360 - July 7th, 2021
- UM School Of Medicine Researchers Receive NIH Avant Garde Award For Out-Of-Box, Innovative Concept To Cure HIV And Treat Co-Existing Addiction -... - July 7th, 2021
- Antengene Announces Acceptance of IND Application in China for the Phase II Clinical Trial of Single-Agent Selinexor for the Treatment of... - July 7th, 2021
- The Top Doctors in the Twin Cities, 2021 - Mpls.St.Paul Magazine - July 7th, 2021
- The stem cell market was valued at USD 14.7 billion in 2020, and it is expected - GlobeNewswire - June 8th, 2021
- Innovative Regenerative Medicine Therapies Safety Comes First - FDA.gov - June 8th, 2021
- Early Promise of AntiCLL-1 CAR T-Cell Therapy Reported in Pediatric AML - Cancer Network - June 8th, 2021
- Part 3: Moving Forward and Keeping Stem Cell Treatments Safe - MedShadow - June 8th, 2021
- In Some Heavily Pretreated Patients with R/R MM Ide-Cel Continues to Show Deep and Durable Responses - Targeted Oncology - June 8th, 2021
- Innovative research refines the treatment of patients with advanced cancers and the use of immunotherapy - Network News, Press Releases - Hackensack... - June 8th, 2021
- Mustang Bio to Host Key Opinion Leader Webinar on MB-106 CD20-Targeted CAR T for the Treatment of High-Risk B-Cell Non-Hodgkin Lymphomas and Chronic... - June 8th, 2021
- Karen Hasty Named Among 2021 Super Women In Business by Memphis Business Journal - UTHSC News - June 8th, 2021
- High Overall Response Rates Achieved With Cirmtuzumab/Ibrutinib in MCL and CLL - Targeted Oncology - June 8th, 2021
- New Data on KEYTRUDA (pembrolizumab) Plus LENVIMA (lenvatinib) Versus Sunitinib in First-Line Treatment for Patients With Advanced Renal Cell... - June 8th, 2021
- Chao family gifts to UCI Health for cancer care top $50 million - UCI News - June 8th, 2021
- Sorrento and Researchers at Karolinska Institutet Have Signed a Research Collaboration Agreement on iPSC-Derived Dimeric - GlobeNewswire - June 8th, 2021
- Responses to Tafasitamab/Lenalidomide in DLBCL Sustained at Three Years - Cancer Network - June 8th, 2021
- The regenerative medicine market size to grow at a CAGR of around 30% during the period - GlobeNewswire - June 8th, 2021
- 'Natural Killer Cells' and Other Promising Cancer Treatments - Barron's - April 18th, 2021
- Capturing the Pandemic Experience in Haiku Poetry - Duke Today - April 18th, 2021
- Chemotherapy for Prostate Cancer: When It's Used and What to Expect - Healthline - April 18th, 2021
- Signs that Chemo Is Working: How Effectiveness Is Measured and Defined - Healthline - April 18th, 2021
- Some experts fear next-generation Covid vaccines may be worse - STAT - April 18th, 2021
- How Long is Chemotherapy? What to Expect - Healthline - April 18th, 2021
- Regenerative Medicine - Stem Cell Therapy Little Rock - March 8th, 2021
- Center for Stem Cell Biology & Regenerative Medicine ... - March 8th, 2021
- Dynamic Stem Cell Therapy Offers Regenerative Medicine - Las Vegas Review-Journal - March 8th, 2021
- Anti-EGFR VHH-armed death receptor ligandengineered allogeneic stem cells have therapeutic efficacy in diverse brain metastatic breast cancers -... - March 8th, 2021
- Research Antibodies Market Size to Reach USD 5325.8 Million by 2027 | Increasing R&D Activities in the Fields of Oncology, Neurobiology, and Stem... - March 8th, 2021
- Microwave Processing Isolates Red Ginseng Compounds That Suppress Lung Cancer Metastasis - Genetic Engineering & Biotechnology News - March 8th, 2021
- Longeveron Expands Enrollment Criteria for its Phase 1 RECOVER Trial Evaluating Lomecel-B Infusion to Treat Acute Respiratory Distress Syndrome due to... - March 8th, 2021
- Be The Match BioTherapies Announces Expansion of Multi-Year Strategic Alliance with Orchard Therapeutics to Support European Commercial Launch of... - March 8th, 2021
- Autologous Stem Cell and Non-Stem Cell Based Therapies Market 2021: Focuses at the key worldwide companies to Define, Describe and Analyses the sales... - March 8th, 2021
- Editing Reproduction: CRISPR and preventing heritable diseases, With Dr. Dietrich Egli and Dr. Sam Sternberg - Columbia University Irving Medical... - March 8th, 2021
- U. Cancer Center pilot projects: investigating cancer connections - The Brown Daily Herald - March 8th, 2021
- COVID-19 can kill heart muscle cells, interfere with contraction Washington University School of Medicine in St. Louis - Washington University School... - March 8th, 2021
- Vaccinating by age groups is unfair, particularly to minorities, advisory panel tells CDC - USA TODAY - March 8th, 2021
- Winter Weather Impacting Blood and Platelet Donations - Milwaukee Community Journal - February 17th, 2021
- Joshua Shirk continues to fight the odds; mom says God placed people where they needed to be to help him - Keyser Mineral Daily News Tribune - February 17th, 2021
- Evotec and Medical Center Hamburg-Eppendorf Enter Partnership to Develop iPSC-Based Tissue Therapy for Heart Failure - GuruFocus.com - February 7th, 2021
- ProgenCell - Stem Cell Therapies offers an updated Stem Cell Therapy for Anti Aging Protocol - PR Web - January 30th, 2021
- Doctors urge immunocompromised to get COVID vaccine when it becomes available - KMTV - 3 News Now - January 30th, 2021
- Autologous Stem Cell and Non Stem Based therapies Market Share, Size 2021 Global Industry Future Trends, Growth, Strategies,, Segmentation, In-depth... - January 30th, 2021
- Studies Indicating T-Cells May Be Needed For Long-Term Protection From The SARS-Cov-2 Virus - PRNewswire - January 30th, 2021
- Researchers use patients' cells to test gene therapy for rare eye disease - National Institutes of Health - January 30th, 2021
- Two Gene Therapies Fix Fault in Sickle Cell Disease and -thalassemia - MD Magazine - January 30th, 2021
- If I Have Cancer, Dementia or MS, Should I Get the Covid Vaccine? - Kaiser Health News - January 30th, 2021
- L-MIND Trial Results Show CD19 Antibody Is Reasonable in R/R DLBCL - Targeted Oncology - January 30th, 2021
- Profile of T Cells, Broadly Neutralizing Antibodies, Anti-Viral Targets: COVID-19 Updates - Bio-IT World - January 30th, 2021
- HealthLynked's The Future of Healthcare Summit Brings Healthcare Experts and Technology Innovators from Around the World to Naples, Florida - WFMZ... - January 30th, 2021
- Tevogen Bio Secures Funding from Team of Doctors to Support Clinical Trials of Its Investigational Curative T Cell Therapy for COVID-19 - PRNewswire - January 25th, 2021
- Novel Treatment Leads to Dog's Recovery - The Bark - January 25th, 2021
- Identification and Targeting of ThomsenFriedenreich and IL1RAP | OTT - Dove Medical Press - January 25th, 2021
- Regenerative Medicine Market Size Worth $74831.35 Million With CAGR of 22.27% By 2024 | Segmented by Product Type, Top Manufacturers, By End-User... - January 25th, 2021
- Immunotherapy Inches Forward in Development of Myeloid Malignancies - OncLive - January 14th, 2021
- Cytovia Therapeutics Partners with National Cancer Institute to Develop Novel Gene-Edited, iPSC-Derived GPC3 CAR NK Cells for the Treatment of Solid... - January 14th, 2021
- Kaleido Biosciences Announces Positive Interim Results of Controlled Study of KB109 in Patients with Mild-to-Moderate COVID-19 - BioSpace - January 14th, 2021
- Doctors Make Medical Breakthrough In Treating Severe Cases Of COVID - CBS San Francisco - January 9th, 2021
- Mana joins the hectic fight against solid tumors with an 'off-the-shelf' candidate angling for an IND this year - Endpoints News - January 9th, 2021
- Versiti Blood Centers and Noodles & Company Serve Up Thanks to Blood Donors - PRNewswire - December 31st, 2020
- Global CAR-T Pipeline Insight Report 2020: Overview, Landscape, Therapeutic Assessment, Current Treatment Scenario and Emerging Therapies -... - December 31st, 2020
- 2020 health care year in review - Crain's Cleveland Business - December 31st, 2020
- The Top 10 FDA Oncology Drug Approvals of 2020 - Curetoday.com - December 31st, 2020
- Gut microbiota: How does it interact with the brain? - Medical News Today - December 31st, 2020
- Numerous Indian American STEM Researchers Named Fellows of American Association for the Advancement of Sciences - India West - December 31st, 2020
- Four years after devastating spinal injury, former St. Paul's football player reunites with caregivers - NOLA.com - December 24th, 2020
- New Combination Therapy Tested By Children's May Offer Hope For Leukemia Patients - WVXU - December 24th, 2020
- Real-time observation helpful in Stem cell for vascular diseases: Study - Hindustan Times - December 21st, 2020
- NurOwn May Be Given to Early ALS Patients in US Who Finished Phase... - ALS News Today - December 21st, 2020
- Follow the Money: Spatial Omics, CAR-NK Cells, AI-Powered Biology - Bio-IT World - December 21st, 2020
- Explained: Process of transporting stem cell from donor to patient for a successful transplant - Firstpost - December 18th, 2020
- Research That Saves Lives: Four COVID-19 Therapies Being Tested at UVA - University of Virginia - December 18th, 2020