Keller Archives

Novel cell therapy treatments offer promise to immune-compromised children

April 18, 2024

teenager receiving an intravenous infusion

In a first-of-its-kind clinical trial, researchers found that intravenous therapies made from virus-specific T-cells (VST) can effectively treat immunocompromised pediatric patients, far surpassing the current standard of care, according to new research published in Nature Communications.

More than 60% of patients in the phase 2 clinical trial led by investigators from Children’s National Hospital and Huntsman Cancer Institute responded to the innovative VST therapy. This new treatment uses blood from healthy donors to manufacture a highly specialized immune therapy that, when given to immune-compromised patients, prompts their immune system to fight off potentially life-threatening viruses, including cytomegalovirus, Epstein-Barr and adenovirus. Without this therapy, estimates suggest that less than 30% of patients would recover, using standard protocols.

“A vast majority of our patients not only responded to the therapy, but they were able to come off their antivirals, which come with extensive side effects,” said Michael Keller, M.D., the paper’s first author and the Translational Research Laboratory director at the Children’s National Cell Enhancement and Technologies for Immunotherapy (CETI) program. “This promising data suggests hope for patients with rare immune-compromising diseases that leave them vulnerable to so much in the world.”

The study brings together experts from the Pediatric Transplantation and Cell Therapy Consortium (PTCTC) and the Primary Immune Deficiency Treatment Consortium (PIDTC) to create the first multi-center, pediatric-consortium trial of adoptive T-cell therapies for viruses. It also represents one of the first to include critically ill patients, who are often excluded from research.

Children’s National leads the way

Working alongside Catherine Bollard, M.D., M.B.Ch.B., director of the Center for Cancer and Immunology Research (CCIR), Dr. Keller and the CCIR team helped build an internationally recognized program, pioneering therapies to prevent complications from viral infections in immunocompromised patients. This includes patients with congenital immune deficiency and others who have undergone bone marrow transplantation for malignancies or non-malignant conditions, such as sickle cell disease.

While doctors can treat some immune-compromised patients for infections with standard antivirals, a small fraction don’t respond. Children’s National is one of a handful of hospitals in the country that has options. Over the last several decades, researchers have found ways to develop VST therapies made from banked T-cells, a more advanced application of how donated red blood cells are used to treat anemia.

In 2017, Drs. Keller and Bollard started collaborating with Michael Pulsipher, M.D.—now with Intermountain Primary Children’s Hospital and the Huntsman Cancer Institute at the University of Utah—to create a multi-institute clinical study. They combined the expertise at Children’s National in producing and banking cell therapy products with the community built around the PTCTC. Ultimately, they launched a clinical trial that was open to 35 centers in the U.S., enrolling 51 patients at 22 hospitals from 2018-2022.

“We wanted to prove that this potentially life-saving therapy could be given safely at regional pediatric centers that had never been able to use this approach before,” said Dr. Pulsipher, who served as the study’s co-principal investigator with Dr. Keller. “We united top experts in this area from the PTCTC and PIDTC and successfully treated some of the most challenging patients ever treated with this approach. Our findings helped define who can benefit the most from this therapy, paving the way for commercial development.”

The Good Manufacturing Practices (GMP) laboratory at Children’s National, led by Patrick Hanley, Ph.D., provided suitable VST therapies for 75 of 77 patients who requested to join the study. Clinical responses were achieved in 62% of patients who underwent stem cell transplants and in 73% of patients who were treated with VST and evaluated one month after their infusion. The paper laid out risks and clinical factors impacting outcomes when third-party donors are used to manufacture the VST therapies.

What’s ahead

Given that researchers are only beginning to develop cell therapies, work remains to understand the many ways they interact with the immune system. In a separate paper also recently published in Nature Communications, members of the multi-institute team documented a case of an infant with severe combined immune deficiency, who faced extremely rare side effects when the VST treatment interfered with her donor bone marrow graft. The case led the team to work with the Food and Drug Administration to identify criteria for VST donors enrolled in this study to mitigate complications.

In the decade ahead, Dr. Bollard sees promise in cell therapies for patients with cancer, immune deficiencies after transplant and dozens of other disorders, including genetic and autoimmune diseases. “Future studies will continue to look at ways to optimize the manufacturing, the administration and the long-term outcomes for these therapies—and to enhance the lifelong impact on our patients,” she said. “When we pair human ingenuity with the power of technology, I see tremendous potential.”

Acknowledgments: This study was funded with a nearly $5 million grant from the California Institute of Regenerative Medicine and was run through the operations center at the Children’s Hospital of Los Angeles, where Dr. Pulsipher was formerly on faculty.

Cell therapy manufacturing process ramps up to meet increased demand for T-cell products

June 17, 2021

The new laboratory space includes floor-to-ceiling windows and brand new, state-of-the-art GMP lab suites.

Since Children’s National Hospital began its pediatric cellular therapy program in 2013, it has received more than $5 million in annual funding, treated over 200 patients, manufactured more than 400 cell-based products and supported over 25 clinical trials.

One of the in-house programs supporting this work is the Good Manufacturing Practices (GMP) facility. Patrick Hanley, Ph.D., chief and director of the cellular therapy program at Children’s National and leader of the GMP laboratory, explained that the first patient received a dose of less than 10 million cells in May 2014. Fast forward to now, the lab uses liters of media, automated bioreactors and multiple staff, making upwards of 12 billion cells per run — a growing production scale that enables many different options. Using cells as an off-the-shelf technology is one of those.

The cell therapy program exports these off-the-shelf products beyond Children’s National to make them available for kids across the country. Catherine Bollard, M.D., MBChB., director of the Center for Cancer and Immunology Research at Children’s National, and Michael Keller, M.D., director of the Translational Research Laboratory in the Program for Cell Enhancement and Technologies for Immunotherapy (CETI) at Children’s National, each led clinical trials with hospitals across the United States, including the first-ever cellular therapy clinical trial run through the Children’s Oncology Group.

To meet the high demand for cell therapy trials at Children’s National, the GMP lab moved to a larger space, doubling the team’s capacity to produce alternative treatment options for patients and facilitate the lab’s ability to support clinical divisions throughout the hospital.

The GMP lab is exploring how to make cell products more consistent — regardless of patient-to-patient variability. They are also hoping to delineate the characteristics that ensure quality cell products, educate other facilities, enhance the overall knowledge of how to safely manufacture these products and make these technologies more available and affordable to the patients who need them.

Among Hanley’s many goals for the GMP lab, one is to improve the transition from when an investigator discovers a product in the translational research lab to when it is manufactured for patients.

“To improve this transition, we have started a process development team that will learn the process alongside the research team, replicate it, and then train the staff who manufacture the product for patients,” said Hanley. “In addition to providing a better training opportunity for the manufacturing staff, it allows us to work with the investigators earlier on to identify changes that will need to be made to translate the products to patients, ultimately resulting in safer, more potent immunotherapy products.”

While cell therapy has seen increased interest in the last 10 years, there are still some challenges in the field, given that it is not as mature as other scientific areas. The lack of trained staff, scalability of cell and gene therapy, the variability between patients and products, delayed FDA approvals and rejection of licensing applications for cell therapy products — are barriers that scientists and companies often face.

“Each of us has a unique immune system, and that means that if we try and make a product from it, it will not behave like any other, so the number of cells, the potency the alloreactivity — it is all different,” said Hanley. “T-cells are a living drug that expand in the body at different rates, are composed of different types of T-cells, and release different cytokines and in different amounts.”

This all ties back to the process development and basic research. The better researchers can characterize the products under development, the more they will know about how the products work and the easier it will be to tie these products to patient outcomes.

Meet some of the Children’s National multidisciplinary experts who join forces to lead the cell therapy space.

Jay Tanna, M.S., quality assurance manager, has extensive experience with drug development at Children’s National as well as Sloan Kettering, another premier cell therapy institution. He has a Masters in Pharmaceutical Manufacturing and a Regulatory Affairs Certification (RAC) in U.S. FDA drugs and biologics regulations from the Regulatory Affairs Professional Society (RAPS).

Kathryn Bushnell, M.T. (ASCP), the cell therapy lab manager, oversees Stem Cell Processing. She has 20 years of experience with hematopoietic progenitor cells and cellular therapy, starting her career as a medical technologist at MD Anderson Cancer Center.

Nan Zhang, Ph.D., assistant director of manufacturing at Children’s National, has worked at Wake Forest and the National Institutes of Health developing various cellular therapies. Zhang chaired the cell processing session at the annual meeting of the American Society of Hematology in 2020.

Abeer Shibli, M.T., is a specialist in the cellular therapy laboratory with extensive experience in the processing of cellular therapy products. She has over 10 years of experience as a medical technologist, is specialized in blood banking and transfusion medicine and is one of the senior technologists in the lab.

Chase McCann, M.S.P.H., Ph.D., is the cell therapy lab lead for manufacturing at Children’s National Hospital. He recently completed his Ph.D. training in Immunology and Microbial Pathogenesis at Weill Cornell Medicine in New York. Much of his graduate research focused on developing and enhancing cellular therapies for HIV while identifying common mechanisms of escape, shared by both HIV and various cancers, which limit the efficacy of current cell therapies. Previously, McCann worked as the laboratory coordinator for the HIV Prevention Trials Network, and now oversees the manufacturing of many cell therapies supporting the many clinical trials currently underway at Children’s National.

Anushree Datar, M.S., the cell therapy lab lead for immune testing and characterization, oversees the release testing of products manufactured in the GMP for safety and function before they can be infused in patients. She also leads a part of the research team investigating the improvement in immune function after cell infusion.

Dr. Bollard is also the director of the Program for Cell Enhancement and Technologies for Immunotherapy and president of the Foundation for the Accreditation for Cellular Therapy (FACT). Additionally, in 2019, she became a member of the Frederick National Laboratory Advisory Committee (FNLAC) for the NIH and an ad hoc member of the Pediatric Oncologic Drugs Advisory Committee (ODAC) for the FDA. She has been an associate editor for the journal Blood since 2014 and in 2020 was appointed editor-in-chief of Blood Advances (starting Fall 2021). Dr. Bollard has 21 years of cell therapy experience as a physician, sponsor and principal investigator.

Dr. Hanley serves as the commissioning editor of the peer-reviewed journal Cytotherapy, as the vice-president-elect (North America) of the International Society of Cell and Gene Therapy (ISCT), and board of directors member at FACT, which provides him visibility into various cell and gene therapies, manufacturing approaches, and other intangibles that make Children’s National facility one of the leaders in the field.

To find the full research program list and their experts, click here.

Lab members celebrate the expansion of the GMP Laboratory.

Immunocompromised pediatric patients show T-cell activity against SARS-CoV-2

May 13, 2021

The study, published in the Journal of Clinical Immunology, suggests that patients with antibody deficiency disorders, including inborn errors of immunity (IEI) and common variable immunodeficiency (CVID), can mount an immune response to SARS-CoV-2 and proposes that vaccination may still be helpful for this population.

According to data from a cohort of adult and pediatric patients with antibody deficiencies, patients that often fail to make protective immune responses to infections and vaccinations showed robust T-cell activity and humoral immunity against SARS-CoV-2 structural proteins. The new study, led by researchers at Children’s National Hospital, is the first to demonstrate a robust T-cell response against SARS-CoV-2 in immunocompromised patients.

“If T-cell responses to SARS-CoV-2 are indeed protective, then it could suggest that adoptive T-cell immunotherapy might benefit more profoundly immunocompromised patients,” said Michael Keller, M.D., director of the Translational Research Laboratory in the Program for Cell Enhancement and Technologies for Immunotherapy (CETI) at Children’s National. “Through our developing phase I T-cell immunotherapy protocol, we intend to investigate if coronavirus-specific T-cells may be protective following bone marrow transplantation, as well as in other immunodeficient populations.”

The study, published in the Journal of Clinical Immunology, showed that patients with antibody deficiency disorders, including inborn errors of immunity (IEI) and common variable immunodeficiency (CVID), can mount an immune response to SARS-CoV-2. The findings propose that vaccination may still be helpful for this population.

“This data suggests that many patients with antibody deficiency should be capable of responding to COVID-19 vaccines, and current studies at the National Institutes of Health and elsewhere are addressing whether those responses are likely to be protective and lasting,” said Dr. Keller.

The T-cell responses in all the COVID-19 patients were similar in magnitude to healthy adult and pediatric convalescent participants.

Kinoshita et al. call for additional studies to further define the quality of the antibody response and the longevity of immune responses against SARS-CoV-2 in immunocompromised patients compared with healthy donors. Currently, there is also very little data on adaptive immune responses to SARS-CoV-2 in these vulnerable populations.

The study sheds light on the antibody and T-cell responses to SARS-CoV-2 protein spikes based on a sample size of six patients, including a family group of three children and their mother. All have antibody deficiencies and developed mild COVID-19 symptoms, minus one child who remained asymptomatic. Control participants were the father of the same family, who tested positive for COVID-19, and another incidental adult (not next of kin) experienced mild COVID-19 symptoms. The researchers took blood samples to test the T-cell response in cell cultures and provided comprehensive statistical analysis of the adaptive immune responses.

“This was a small group of patients, but given the high proportion of responses, it does suggest that many of our antibody deficient patients are likely to mount immune responses to SARS-CoV-2,” said Dr. Keller. “Additional studies are needed to know whether other patients with primary immunodeficiency develop immunity following COVID-19 infection and will likely be answered by a large international collaboration organized by our collaborators at the Garvan Institute in Sydney.”

PRAME-specific T cell product may facilitate rapid treatment in cancer settings

April 12, 2021

PRAME is a cancer-testis antigen that plays a role in cancer cell proliferation and survival and is overexpressed in many human malignancies, including Wilms tumor. “Wilms Tumor (Nephroblastoma)” by euthman is licensed under CC BY 2.0.

Generated preferentially expressed antigen in melanoma (PRAME)-specific T cells from healthy donors can kill PRAME-expressing tumor cells in vitro, researchers at Children’s National Hospital found. Several novel epitopes, which are antigens that are recognized by the immune system, were also identified for enhanced matching, making this a potential therapeutic option for a broader patient group, according to a study published in Cytotherapy.

PRAME is a cancer-testis antigen that plays a role in cancer cell proliferation and survival and is overexpressed in many human malignancies, including melanoma, leukemia, sarcoma, renal cell cancer and Wilms tumor. PRAME also acts as a foreign substance in the body that can trigger the immune system by activating T cells, making it a good target for anticancer immunotherapy — especially for immunocompromised patients.

“The development of an effective off-the-shelf adoptive T-cell therapy for patients with relapsed or refractory cancers expressing PRAME antigen requires the identification of epitopes essential to the adaptive immune response, which are presented by major histocompatibility complex (MHC) class I and II, and are then recognized by the manufactured PRAME-specific T cell product,” said Amy Hont, M.D., oncologist for the Center for Cancer and Immunology Research at Children’s National Hospital. “We, therefore, set out to extend the repertoire of HLA-restricted PRAME peptide epitopes beyond the few already characterized and demonstrate the cytotoxic activity of PRAME-specific T cells to tumor cells known to express PRAME.”

Immunotherapy options for pediatric patients with high-risk malignancies, especially solid tumors, are few. Tumor-associated antigen-specific T cells (TAA-T) offer a therapeutic option for these patients, and Children’s National is building upon the success of the ongoing clinical trials to optimize this therapy and improve the treatment of our patients.

“These findings will also benefit patients because it better informs the pre-clinical studies of third party TAA-T to treat high-risk malignancies, so that we can move more quickly and safely to clinical trials,” said Dr. Hont.

Stanojevic et al. describes that the T-cell products killed partially HLA-matched tumors, and that this enhanced disintegration of tumor cells compared with non-specific T cells suggests an anti-tumor potential for a clinical trial evaluation to determine the safety and efficacy. Further research about the PRAME-specific T cells will help inform a treatment alternative for patients with solid tumors in the future.

The researchers generated a PRAME-specific T cell bank from healthy donor cells and demonstrated anti-tumor cytolytic activity against tumor lines partially HLA-matched to the T cells and known to express PRAME. By using epitope mapping, they identified several novel epitopes restricted to MHC class I or MHC class II to further inform HLA matching.

“Defining PRAME-specific T cells beyond HLA epitopes could be useful when developing T-cell therapies for worldwide application,” Stanojevic et al. write. “Moreover, creating off-the-shelf products has many potential advantages since such products are readily available for the treatment of patients with aggressive disease or patients for whom an autologous product cannot be manufactured.”

Additional authors from Children’s National are Maja Stanojevic, M.D., Ashley Geiger, M.S., Samuel O’Brien, Robert Ulrey, M.S., Melanie Grant, Ph.D., Anushree Datar, M.S., Ping-Hsien Lee, Ph.D., Haili Lang, M.D., Conrad R.Y. Cruz, M.D., Ph.D., Patrick J. Hanley, Ph.D., A. John Barrett, M.D, Michael D. Keller, M.D., and Catherine M. Bollard, M.D., M.B.Ch.B.

T-cells show promise to protect vulnerable patients from COVID-19 infection

October 26, 2020

Children’s National Hospital immunotherapy experts have found that T-cells taken from the blood of people who recovered from a COVID-19 infection can be successfully multiplied in the lab and maintain the ability to effectively target proteins that are key to the virus’s function.

Children’s National Hospital immunotherapy experts have found that T-cells taken from the blood of people who recovered from a COVID-19 infection can be successfully multiplied in the lab and maintain the ability to effectively target proteins that are key to the virus’s function. Their findings were published Oct. 26, 2020, in Blood.

“We found that many people who recover from COVID-19 have T-cells that recognize and target viral proteins of SARS-CoV-2, giving them immunity from the virus because those T-cells are primed to fight it,” says Michael Keller, M.D., a pediatric immunology specialist at Children’s National Hospital, who led the study. “This suggests that adoptive immunotherapy using convalescent T-cells to target these regions of the virus may be an effective way to protect vulnerable people, especially those with compromised immune systems due to cancer therapy or transplantation.”

Based on evidence from previous phase 1 clinical trials using virus-targeting T-cells “trained” to target viruses such as Epstein-Barr virus, the researchers in the Cellular Therapy Program at Children’s National hypothesized that the expanded group of COVID-19 virus-targeting T-cells could be infused into immunocompromised patients, helping them build an immune response before exposure to the virus and therefore protecting the patient from a serious or life-threatening infection.

“We know that patients who have immune deficiencies as a result of pre-existing conditions or following bone marrow or solid organ transplant are extremely vulnerable to viruses like SARS-CoV-2,” says Catherine Bollard, M.D., M.B.Ch.B., senior author of the study and director of the novel cell therapies program and the Center for Cancer and Immunology Research at Children’s National. “We’ve seen that these patients are unable to easily clear the virus on their own, and that can prevent or delay needed treatments to fight cancer or other diseases. This approach could serve as a viable option to protect or treat them, especially since their underlying conditions may make vaccines for SARS-CoV-2 unsafe or ineffective.”

The T-cells were predominantly grown from the peripheral blood of donors who were seropositive for SARS-CoV-2. The study also identified that SARS-CoV-2 directed T-cells have adapted to predominantly target specific parts of the viral proteins found on the cell membrane, revealing new ways that the immune system responds to COVID-19 infection.

Current vaccine research focuses on specific proteins found mainly on the “spikes” of the coronavirus SARS-CoV-2. The finding that T-cells are successfully targeting a membrane protein instead may add another avenue for vaccine developers to explore when creating new therapeutics to protect against the virus.

“This work provides a powerful example of how both scientific advances and collaborative relationships developed in response to a particular challenge can have broad and unexpected impacts on other areas of human health,” says Brad Jones, Ph.D., an associate professor of immunology in medicine in the Division of Infectious Diseases at Weill Cornell Medicine and co-author on the study, whose lab focuses on HIV cure research. “I began working with Dr. Bollard’s team several years ago out of our shared interest in translating her T-cell therapy approaches to HIV. This put us in a position to quickly team up to help develop the approach for COVID-19.”

The Cellular Therapy Program is now seeking approval from the U.S. Food and Drug Administration for a phase 1 trial that will track safety and effectiveness of using COVID-19-specific T-cells to boost the immune response in patients with compromised immune systems, particularly for patients after bone marrow transplant.

Tailored T-cell therapies neutralize viruses that threaten kids with PID

November 18, 2019

t-cells

Tailored T-cells specially designed to combat a half dozen viruses are safe and may be effective in preventing and treating multiple viral infections, according to research led by Children’s National Hospital faculty.

Catherine Bollard, M.B.Ch.B., M.D., director of the Center for Cancer and Immunology Research at Children’s National and the study’s senior author, presented the teams’ findings Nov. 8, 2019, during a second-annual symposium jointly held by Children’s National and the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH). Children’s National and NIAID formed a research partnership in 2017 to develop and conduct collaborative clinical research studies focused on young children with allergic, immunologic, infectious and inflammatory diseases. Each year, they co-host a symposium to exchange their latest research findings.

According to the NIH, more than 200 forms of primary immune deficiency diseases impact about 500,000 people in the U.S. These rare, genetic diseases so impair the person’s immune system that they experience repeated and sometimes rare infections that can be life threatening. After a hematopoietic stem cell transplantation, brand new stem cells can rebuild the person’s missing or impaired immune system. However, during the window in which the immune system rebuilds, patients can be vulnerable to a host of viral infections.

Because viral infections can be controlled by T-cells, the body’s infection-fighting white blood cells, the Children’s National first-in-humans Phase 1 dose escalation trial aimed to determine the safety of T-cells with antiviral activity against a half dozen opportunistic viruses: adenovirus, BK virus, cytomegalovirus (CMV), Epstein-Barr virus (EBV), Human Herpesvirus 6 and human parainfluenza-3 (HPIV3).

Eight patients received the hexa-valent, virus-specific T-cells after their stem cell transplants:

Three patients were treated for active CMV, and the T-cells resolved their viremia.
Two patients treated for active BK virus had complete symptom resolution, while one had hemorrhagic cystitis resolved but had fluctuating viral loads in their blood and urine.
Of two patients treated prophylactically, one developed EBV viremia that was treated with rituximab.

Two additional patients received the T-cell treatments under expanded access for emergency treatment, one for disseminated adenoviremia and the other for HPIV3 pneumonia. While these critically ill patients had partial clinical improvement, they were being treated with steroids which may have dampened their antiviral responses.

“These preliminary results show that hexaviral-specific, virus-specific T-cells are safe and may be effective in preventing and treating multiple viral infections,” says Michael Keller, M.D., a pediatric immunologist at Children’s National and the lead study author. “Of note, enzyme-linked immune absorbent spot assays showed evidence of antiviral T-cell activity by three months post infusion in three of four patients who could be evaluated and expansion was detectable in two patients.”

In addition to Drs. Bollard and Keller, additional study authors include Katherine Harris M.D.; Patrick J. Hanley Ph.D., assistant research professor in the Center for Cancer and Immunology; Allistair Abraham, M.D., a blood and marrow transplantation specialist; Blachy J. Dávila Saldaña, M.D., Division of Blood and Marrow Transplantation; Nan Zhang Ph.D.; Gelina Sani BS; Haili Lang MS; Richard Childs M.D.; and Richard Jones M.D.

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Children’s National-NIAID 2019 symposium presentations

“Welcome and introduction”
H. Clifford Lane, M.D., director of NIAID’s Division of Clinical Research

“Lessons and benefits from collaboration between the NIH and a free-standing children’s hospital”
Marshall L. Summar, M.D., director, Rare Disease Institute, Children’s National

“The hereditary disorders of PropionylCoA and Cobalamin Metabolism – past, present and future”
Charles P. Venditti, M.D., Ph.D., National Human Genome Research Institute Collaboration

“The road(s) to genetic precision therapeutics in pediatric neuromuscular disease: opportunities and challenges”
Carsten G. Bönnemann, M.D., National Institute of Neurological Disorders and Stroke

“Genomic diagnostics in immunologic diseases”
Helen Su, M.D., Ph.D., National Institute of Allergy and Infectious Diseases

“Update on outcomes of gene therapy clinical trials for X-SCID and X-CGD and plans for future trials”
Harry Malech, M.D., National Institute of Allergy and Infectious Diseases

“Virus-specific T-cell therapies: broadening applicability for PID patients”
Catherine Bollard, M.D., Children’s National

“Using genetic testing to guide therapeutic decisions in Primary Immune Deficiency Disease”
Vanessa Bundy, M.D., Ph.D., Children’s National

Panel discussion moderated by Lisa M. Guay-Woodford, M.D.
Drs. Su, Malech, Bollard and Bundy
Morgan Similuk, S.C.M., NIAID
Maren Chamorro, Parent Advocate

“Underlying mechanisms of pediatric food allergy: focus on B cells
Adora Lin, M.D., Ph.D., Children’s National

“Pediatric Lyme outcomes study – interim update”
Roberta L. DeBiasi, M.D., MS, Children’s National

“Molecular drivers and opportunities in neuroimmune conditions of pediatric onset”
Elizabeth Wells, M.D., Children’s National

Virus-specific t-cells show promise before transplant in SCID patients

June 22, 2018

“Today, we know that virus-specific T-cells can help protect patients from dangerous viruses after stem cell transplants,” says Michael Keller, M.D. “Through this research, we used the same therapy and approach, but applied it pre-transplant with the hope of providing the same benefit of protection against life-threatening viruses to patients who need it the most.”

Experts at Children’s National Health System have been successfully studying the use of virus-specific T-cells (VST) to help protect immunocompromised patients from life-threatening viruses after bone marrow transplants. Research published recently in the Biology of Blood and Marrow Transplantation presents promising new findings from testing the use of these same VSTs before transplant to help give patients with severe combined immunodeficiency (SCID) a better chance at long-term survival.

Babies born with SCID are highly susceptible to severe infections that are often fatal if not treated with immune-restoring treatments, like hematopoietic stem cell transplants (HSCT). However, undergoing an HSCT with an infection present has shown to lead to a decrease in survival at two years old for SCID patients when compared to those who start the HSCT infection-free. The study lead, Michael Keller, M.D., hypothesized that the success of HSCTs in SCID patients may be improved by controlling severe viral infections before the patient undergoes the transplant.

“Today, we know that virus-specific T-cells can help protect patients from dangerous viruses after stem cell transplants,” says Dr. Keller. “Through this research, we used the same therapy and approach, but applied it pre-transplant with the hope of providing the same benefit of protection against life-threatening viruses to patients who need it the most.”

Dr. Keller administered the VSTs from a healthy third-party donor in a five-month-old infant fighting adenovirus before undergoing a HSCT to cure him of SCID. Today, the baby is healthy and has a normal immune system. Ultimately, this research shows that the use of VSTs is likely safe in the pre-HSCT period in patients with SCID and may be an effective therapy for viral infections when they are resistant to antiviral therapy.

“I believe this VST therapy could make a real and lasting impact for patients with SCID,” said Dr. Keller. “It gives them a real chance at a long life.”

Training t-cells, essential players in the immune system, to fight a trio of viruses

May 26, 2016

What’s Known
Following treatment, patients with leukemia, lymphoma, and other cancers may receive a transplant in order to restore their body’s natural ability to fight infection and, sometimes, such transplants are a component of leukemia treatment. (Leukemia is the second most common blood cancer, after lymphoma, and its incidence rate has increased by 0.2 percent annually from 2002 to 2011.) A stem cell or cord blood transplant restores the body’s ability to produce infection-fighting white blood cells. After such transplants, however, patients can face heightened risk of developing a life-threatening infection with such viruses as adenovirus, cytomegalovirus, or Epstein-Barr virus.

What’s New
A head-to-head comparison of two strategies to thwart such viral infections shows that both approaches leverage the power of multivirus-specific, donor-derived T-cells (mCTL), which are highly skilled at recognizing foreign invaders. The research team, made up of nine scientists and clinicians affiliated with Children’s National Health System, grew personalized T-cells from peripheral blood (PB) of adult donors who were seropositive for CMV and also coaxed T-cells to grow from naïve cord blood (CB). PB-derived cells have long memories of past battles; naïve CB-derived cells need additional training to acquire such skills. From 35 to 384 days after their stem cell or cord blood transplant, 13 patients were infused with PB mCTL and 12 patients were infused with CB mCTL. Within four weeks, patients experienced up to a 160-fold increase in virus-specific T-cells, which coincided with their response to therapy. Overall response rate was 81 percent.

Questions for Future Research
Q: Could T-cells be personalized to attack other viruses that infect patients post-transplant, such as human parainfluenza virus and BK polyomavirus, providing the potential to target five viruses in a single infusion?
Q: Could the proteins that are used to train T-cells to attack certain viruses also be used to create a personalized approach to tumor suppression?

Source: “A Phase 1 Perspective: Multivirus-Specific T Cells From Both Cord Blood and Bone Marrow Transplant Donors.” Hanley, P., M. D. Keller, M. Martin Manso, C. Martinez, K. Leung, C.R. Cruz, C. Barese, S. McCormack, M. Luo, R.A. Krance, D. Jacobsohn, C. Rooney, H. Heslop, E.J. Shpall, and C. Bollard. Presented during the International Society for Cellular Therapy 2016 Annual Meeting, Singapore. May 26, 2016.

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