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Michael Keller

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

Michael Keller

“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.”

Anthony Sandler

Treatment of neuroblastoma with immunotherapy and vaccine combination shows promise

Anthony Sandler

“Treatment options like these that help the body use its own immune system to fight off cancer are incredibly promising, and we look forward to continuing this work to understand how we can best help our patients and their families,” said Anthony Sandler, M.D.

Despite being the most common extracranial solid tumor found in children and having multiple modes of therapy, neuroblastoma continues to carry a poor prognosis. However, a recent cutting-edge pre-clinical study, PD-L1 checkpoint inhibition and anti-CTLA-4 whole tumor cell vaccination counter adaptive immune resistance: A mouse neuroblastoma model that mimics human disease, published in PLOS Medicine shows the first signs of success in treating high-risk neuroblastoma, a promising step not only for neuroblastoma patients, but potentially for other types of cancer and solid tumors as well. While the research was conducted on mouse models and is in the early stages, the lead author of the study, Anthony Sandler, M.D., senior vice president and surgeon-in-chief of the Joseph E. Robert, Jr., Center for Surgical Care at Children’s National, believes these findings are an encouraging development for the field.

The treatment method combines a novel personalized vaccine and a combination of drugs that target checkpoint inhibitors enabling the immune system to identify and kill cancer cells. When these checkpoints are blocked, it’s similar to taking the brakes off the immune system so that the body’s T cells can be primed by the vaccine, identify the tumor and allow for targeted tumor cell killing. The vaccine then brings in reinforcements to double down on the attack, helping to eradicate the tumor. The vaccine could also be used as a way to prevent recurrence of disease. After a patient has received the vaccine, the T cells would live in the body, remembering the tumor cells, and attack reemerging cancer in a similar way that a flu vaccine helps fight off the flu virus.

“Treatment options like these that help the body use its own immune system to fight off cancer are incredibly promising, and we look forward to continuing this work to understand how we can best help our patients and their families,” said Dr. Sandler.

Allistair Abraham

Q&A with leading blood and marrow transplantation specialist

Allistair Abraham

Children’s National Health System is proud to be the home of some of the world’s leading hematology experts, including Allistair Abraham, M.D., blood and marrow transplantation specialist within the Center for Cancer and Blood Disorders, who was recently selected to participate in the American Society of Hematology-Harold Amos Medical Faculty Development Program (ASH-AMFDP). Designed to increase the number of underrepresented minority scholars in the field of hematology, the ASH-AMFDP has awarded Dr. Abraham $420,000 that includes an annual stipend and research grant over the next four years. Here, Dr. Abraham tells us more about his research and what it means for the future of patients with sickle cell disease.

Q: What does this award mean to you?
A: This award comes at a critical time in my early career as I learn how to become an independent grant-funded researcher. It gives me an opportunity to dedicate 70 percent of my time to research for the next four years, during which I will hone my research skills and have access to highly accomplished mentors at Children’s National and from the ASH-AMFDP faculty.

Q: Your research for this grant focuses on improving curative hematopoietic stem cell transplantation for sickle cell disease. Why do they need to be improved?

A: Sickle cell disease causes significant health problems for children, which can worsen as they become adults, and even shorten their lifespan. Curative therapies to date are limited for many patients since most do not have a suitably matched donor for a curative bone marrow transplant. Many of us in the field hope we can provide a safe option for as many patients as possible so they can be cured in childhood and not have to face the negative impacts of the disease as they grow older.

Q: You will also be evaluating virus-specific T-cell (VST) recovery after transplantation. What will this mean for patients?

A: As we explore more transplant donor options such as unrelated donors and mismatched family donors, we have observed delayed immune system recovery. Viral infections are particularly problematic, as they can be life-threatening and respond poorly to available medications. Ultimately, a recovered immune system would address the infection problem. We hope to generate immune cells that are protective against viruses from the transplant donor and give them to patients as part of their transplant procedure.

Q: How do you envision your research improving the future of treatment for sickle cell patients?

A: My hope is that we get closer to having a safer transplant option for most patients who, despite optimal therapy, continue to suffer from complications of sickle cell disease. Ideally, these transplants would not only be widely available, but the treatment would also be simplified to the point where most of the therapy could take place in an outpatient setting.

Q:  Why did you decide to work in this field?

A:  Sickle cell disease has lagged behind other disorders in terms of new treatment strategies for quite some time. I experienced this as a medical trainee and struggled when parents would ask me to “do something” for their child when most of the time all I could offer was pain medication. In the last five years or so, there has been more focus on sickle cell disease from the field and the community, so now is the time to work toward developing a widely available cure.

American Society of Hematology logo

Leading blood disorder experts from Children’s National convene in Atlanta for 59th American Society of Hematology annual meeting

In early December 2017, more than 25,000 attendees from around the world, including several experts from Children’s National Health System, convened in Atlanta for the American Society of Hematology’s annual meeting and exposition, the world’s premiere hematology event. For four days, physicians, nurses and other healthcare professionals attended sessions, listened to speakers and collaborated with each other, focusing on enhancing care and treatment options for patients with blood disorders and complications, including leukemia, sickle cell disease and transplants.

As nationally recognized leaders in the field, the Children’s National team led educational sessions and gave keynote speeches highlighting groundbreaking work underway at the hospital, which sparked engaging and productive conversations among attendees. Highlights from the team include:

  • Catherine Bollard, M.D., M.B.Ch.B., Director of the Center for Cancer and Immunology Research, educating global experts on cellular immunotherapy for non-Hodgkin lymphoma.
  • Kirsten Williams, M.D., bone and marrow transplant specialist, presenting novel work utilizing TAA-specific T cells for hematologic malignancies with Dr. Bollard, the sponsor of this first-in-man immunotherapy; moderating sessions on immunotherapy and late complications and survivorship after hematopoietic stem cell transplantation (HSCT).
  • Allistair Abraham, M.D., blood and marrow transplantation specialist, moderating a session on hemoglobinopathies.
  • David Jacobsohn, M.D., ScM, Division Chief of Blood and Marrow Transplantation, moderating a session on allogeneic transplantation results.
  • Naomi Luban, M.D., hematologist and laboratory medicine specialist, introducing a plenary speaker on the application of CRISPR/Cas 9 technology for development of diagnostic reagents for diagnosis of alloimmunization from stem cells.

Additional presentations from the Children’s National team included an oral abstract on the hospital’s work to improve hydroxyurea treatment for sickle cell disease by pediatric resident Sarah Kappa, M.D., who also received an ASH Abstract Achievement Award; another key session on hemoglobinopathies moderated by Andrew Campbell, M.D., director of the Comprehensive Sickle Cell Disease Program; an abstract on the clinical use of CMV- specific T-cells derived from CMV-native donors, presented by Patrick Hanley, Ph.D.; a leukemia study presented by Anne Angiolillo, M.D., oncologist; and a presentation about pain measurement tools in sickle cell disease by Deepika Darbari, M.D., hematologist.

Visit the ASH website to learn more about the conference attendees and their research.

Advances in T-cell immunotherapy at ISCT

Healthy Human T Cell

T-cell immunotherapy, which has the potential to deliver safer, more effective treatments for cancer and life-threatening infections, is considered one of the most promising cell therapies today. Each year, medical experts from around the world – including leaders in the field at Children’s National Health System – gather at the International Society for Cellular Therapy (ISCT) Conference to move the needle on cell therapy through several days of innovation, collaboration and presentations.

Dr. Catherine Bollard, Children’s National chief of allergy and immunology and current president of ISCT, kicked off the week with a presentation on how specific approaches and strategies have contributed to the success of T-cell immunotherapy, a ground-breaking therapy in this fast-moving field.

Later in the week, Dr. Kirsten Williams, a blood and marrow transplant specialist, presented encouraging new findings, demonstrating that T-cell therapy could be an effective treatment for leukemia and lymphoma patients who relapse after undergoing a bone marrow transplant. Results from her phase 1 study showed that four out of nine patients achieved complete remission. Other medical options for the patients involved – those who relapsed between 2 and 12 months post-transplant – are very limited. Looking to the future, this developing therapy, while still in early stages, could be a promising solution.

Other highlights include:

  • Both Allistair Abraham, blood and marrow transplantation specialist, and Dr. Michael Keller, immunologist, presented oral abstracts, the former titled “Successful Engraftment but High Viral Reactivation After Reduced Intensity Unrelated Umbilical Cord Blood Transplantation for Sickle Cell Disease” and the latter “Adoptive T Cell Immunotherapy Restores Targeted Antiviral Immunity in Immunodeficient Patients.
  • Patrick Hanley engaged attendees with his talk, “Challenges of Incorporating T-Cell Potency Assays in Early Phase Clinical Trials,” and his poster presentation “Cost Effectiveness of Manufacturing Antigen-Specific T-Cells in an Academic GMP Facility.” He also co-chaired a session titled “Early Stage Professionals Session 1 – Advanced Strategic Innovations for Cell and Gene Therapies.”
  • To round out this impressive group, Shabnum Piyush Patel gave a talk on genetically modifying HIV-specific T-cells to enhance their anti-viral capacity; the team plans to use these HIV-specific T-cells post-transplant in HIV-positive patients with hematologic malignancies to control their viral rebound.

This exciting team is leading the way in immunology and immunotherapy, as evidenced by the work they shared at the ISCT conference and their ongoing commitment to improving treatments and outcomes for patients at Children’s National and across the country. To learn more about the team, visit the Center for Cancer and Blood Disorders site.

Cell therapy virtuoso: Catherine Bollard

Catherine Bollard

In the Medicine Maker piece, Cell Therapy Virtuoso, Children’s National Medical System’s Chief of Allergy and Immunology, Catherine Bollard M.D., discusses why she chose a career in medicine, the personal experience that ignited her interest in cell therapies, and her insights on the current state and future of the immunotherapy field. Highlights from the interview include:

  • On the promise of T-cell therapy: “We’ve now developed several T-cell therapies that give complete remission rates of approximately 75% and two-year progression-free survival rates ranging from 50 percent to over 90 percent depending on the patient population.”
  • Regarding the future of immunotherapy: “The field has expanded dramatically over the last 25 years. In particular, T-cell therapies for cancer have grown rapidly and now the field is expanding into other areas, such as regulatory T-cells for autoimmune disease and virus T-cells for HIV. Given what the immune system can do, the applications are almost limitless.”

Dr. Bollard was featured for her role as president of the International Society for Cellular Therapy.

cord blood

T-cell therapy success for relapsing blood cancer

cord blood

A unique immunotherapeutic approach that expands the pool of donor-derived lymphocytes (T-cells) that react and target three key tumor-associated antigens (TAA) is demonstrating success at reducing or eliminating acute leukemias and lymphomas when these cancers have relapsed following hematopoietic stem cell transplant (HSCT).

“There’s currently a less than 10 percent chance of survival for a child who relapses leukemia or lymphoma after a bone marrow transplant—in part because these patients are in a fragile medical condition and can’t tolerate additional intense therapy,” says Kirsten Williams, M.D., a blood and marrow transplant specialist in the Division of Hematology at Children’s National Health System, and principal investigator of the Research of Expanded multi-antigen Specifically Oriented Lymphocytes for the treatment of VEry High Risk Hematopoietic Malignancies (RESOLVE) clinical trial.

The unique manufactured donor-derived lymphocytes used in this multi-institutional Phase 1 dose-ranging study are receptive to multiple tumor-associated antigens within the cell, including WT1, PRAME, and Survivin, which have been found to be over-expressed in myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), B-cell AML/MDS, B-cell acute lymphoblastic leukemia (ALL), and Hodgkins lymphoma. Modifying the lymphocytes for several antigens, rather than a single target, broadens the ability of the T-cells to accurately target and eradicate cancerous cells.

Preliminary results demonstrate a 78 percent response rate to treatment, and a 44 percent rate of total remission for participating patients. To date, nine evaluable patients with refractory and relapsed AML/MDS, B-cell ALL, or Hodgkins lymphoma have received 1-3 infusions of the expanded T-cells, and of those, seven have responded to the treatment, showing reduction in cancer cells after infusion with little or no toxicity. All of these patients had relapse of their cancer after hematopoietic cell transplantation. The study continues to recruit eligible patients, with the goal of publishing the full study results within the next 12 months.

“Our preliminary data also shows that this new approach has few if any side effects for the patient, in part because the infused T-cells target antigens that are found only in cancer cells and not found in healthy tissues,” Dr. Williams notes.

The approach used to expand existing donor-derived TAA-lymphocytes, rather than using unselected T cells or genetically modified T-cells as in other trials, also seems to reduce the incidence of post infusion graft versus host disease and other severe inflammatory side effects. Those side effects typically occur when the infused lymphocytes recognize healthy tissues as foreign and reject them or when the immune system reacts to the modified elements of the lymphocytes, she adds.

“These results are exciting because they may present a truly viable option for the 30 to 40 percent of children who will relapse post-transplant,” Dr. Williams concludes. “Many of the patients who participated were given two options: palliative care or this trial. To see significant success and fewer side effects gives us, and families with children facing relapsing leukemia, some hope for this new treatment.”

Dr. Williams discussed the early outcomes of the RESOLVE trial during an oral presentation at the American Society for Blood and Marrow Transplantation meeting on February 22, 2017.

“The early indicators are very promising for this patient population,” says Catherine Bollard, M.D., M.B.Ch.B., Chief of the Division of Allergy and Immunology, Director of the Program for Cell Enhancement and Technologies for Immunotherapy (CETI) at Children’s National, and senior author of the study. “If we can achieve this, and continue to see good responses with few side effects, it’s possible these methods could become a viable alternative to HSCT for patients with no donor match or who aren’t likely to tolerate transplant.”

This is one of the first immunotherapeutic approaches to successfully capitalize on the natural ability of human T-cells to kill cancer, though previous research has shown significant success for this approach in reducing the deadly impact of several viruses, including Epstein-Barr virus, adenovirus, and cytomegalovirus, post HSCT. These new findings have led to the development of additional clinical trials to investigate applications of this method of TAA-lymphocyte manufacture and infusion for pre-HSCT MDS/AML, B-cell ALL, Hodgkins Lymphoma, and even some solid tumors.

New research shows success training t-cells to recognize and fight life-threatening viruses

Children's is the only U.S. pediatric hospital that manufactures specialized T-cells from native cord blood

Patients with leukemia, lymphoma, other cancers, and genetic disorders who receive stem cell or cord blood transplants face the post-transplant risk of developing a life-threatening infection with adenovirus, cytomegalovirus (CMV), or Epstein-Barr virus (EBV).

The study reports the results of a head-to-head comparison of two powerful immunotherapeutic strategies to thwart such viral infections. Both therapeutic approaches leverage the power of multivirus-specific, donor-derived T-cells (mCTL), which are highly skilled at recognizing foreign invaders and, in the case of the peripheral blood cells, have long memories of past battles.

The award-winning paper, “Multivirus-Specific T Cells From Both Cord Blood and Bone Marrow Transplant Donors” was presented during the International Society for Cellular Therapy (ISCT) 2016 Annual Meeting, held from May 25 through May 28, in Singapore. The abstract’s lead author, Patrick J. Hanley, PhD, Laboratory Facility Director of Children’s Cellular Therapy and Stem Cell Processing facility, was recognized by ISCT with a Young Investigator award during the meeting.

Nine research scientists and clinicians affiliated with Children’s National Health System are co-authors of a paper, including Michael D. Keller, MD, the lead clinical investigator of the peripheral blood T-cell study, and Catherine M. Bollard, MBChB, MD, the study’s sponsor and Director of Children’s National Program for Cell Enhancement and Technologies for Immunotherapy.

After certain treatments, some cancer patients’ bodies are stripped of their natural ability to fight infection. The stem cell or the cord blood transplant restores the body’s ability to produce a full complement of blood cells, including infection-fighting white blood cells. As a further boost to these patients, the T-cells are trained to spot and neutralize all three potentially lethal viruses (CMV, EBV, and adenovirus) simultaneously. The personalized cell therapy can be accomplished in a single infusion and administered in the outpatient setting.

In the phase I perspective study, the personalized T-cells were grown from peripheral blood (PB) of adult donors who were seropositive for CMV, a relative of the virus that causes chickenpox, and were also coaxed to grow from naïve cord blood (CB). These naïve cells need additional training since they have never been to battle.

Since the mid-1990s, PB has been shown to be effective for such use. Hanley says that fewer than one dozen facilities in the United States perform PB antiviral T-cell infusions. Of that selective group, Children’s National is the only U.S. location that also grows the specialized T-cells from naïve CB, a procedure that takes a bit longer to accomplish but can help patients whose blood type is in short supply.

Thirteen patients were infused with PB mCTL, and 12 patients were infused with the T-cells derived from cord blood. Patients received their transfusions from 35 to 384 days after their stem cell or cord blood transplant. Within four weeks, the research team saw up to a 160-fold increase in virus-specific T-cells, a development that coincided with patients’ response to therapy. “The overall … response rate in both groups was 81 percent,” writes Hanley and colleagues.

Eight patients had a complete response. Five had a partial response. Nine remain free of infection/reactivation. What’s more, the patients’ restored immunity was durable with at least one patient remaining free of infection two years after treatment – without the need for pharmaceuticals administered in a hospital setting, which exacts a higher overall cost to the healthcare system.

“This study demonstrates that mCTL derived from the PB of seropositive donors, as well as the CB of virus naïve donors, expand in vivo and are active against multiple viruses. Furthermore, by restoring immunity to multiple viruses simultaneously, the need for continued prophylaxis with pharmacotherapy is eliminated, thus, improving the efficiency and cost-effectiveness of protecting SCT and CBT recipients from these potentially lethal viruses,” Hanley and co-authors conclude.

Related Resources: Research at a Glance