Genome Editing and Cellular Therapies Show Promise for Treating Blood Disorders, Cancers

Researchers test CRISPR in blood disorders and extend CAR-T therapy to benefit more patients

Date of Release: Dec. 5, 2020 

WASHINGTON /PRNewswire/ — Three studies being presented during the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition report promising results in the use of cutting-edge genome editing and cellular therapies for hard-to-treat blood disorders and cancers.

In the first study, researchers used CRISPR/Cas9 to treat two inherited blood disorders, beta thalassemia and sickle cell disease (SCD). The trial, which demonstrated remarkable improvements in all seven participants, is the first time this revolutionary approach has been used successfully in these patient populations.

“Given that the only FDA-approved cure for sickle cell disease, a bone marrow transplant, is not widely accessible, having another curative option would be life-changing for a large number of the sickle cell disease population,” said press briefing moderator Catherine Bollard, MD, of Children’s National Research Institute and George Washington University. “While longer follow-up data are needed, this study is extremely exciting for the field.”

The second two studies point to new opportunities to reach a broader patient population with chimeric antigen receptor T-cell (CAR-T) therapy. While this cellular immunotherapy has dramatically improved outcomes for patients with some blood cancers, it does not work in all patients. One of the new studies offers an explanation as to why some patients do not respond to CD19-CAR-T therapy and suggest a way to overcome this resistance. The other study suggests CD19-CAR-T may be a viable option for some patients with high-risk non-Hodgkin lymphoma who have not responded to standard treatments.

“Getting more data on CD19-CAR-T therapy in the high-risk non-Hodgkin lymphoma population is very important,” said Dr. Bollard. “We know that CD19-CAR-T therapy does not work for some patients, so these studies underscore the need to better understand the immune evasion mechanisms T cells might be susceptible to and not just focus on their role as a vehicle for the CAR. Doing so may improve our capacity to administer effective T-cell immunotherapies.”

This press briefing will take place on Saturday, December 5, at 9:30 a.m. Pacific time on the ASH annual meeting virtual platform.

CRISPR-based Gene Editing Shows Early Promise in First Clinical Trials
4: Safety and Efficacy of CTX001 in Patients with Transfusion-Dependent β- Thalassemia and Sickle Cell Disease: Early Results from the Climb THAL-111 and Climb SCD-121 Studies of Autologous CRISPR-CAS9–Modified CD34+ Hematopoietic Stem and Progenitor Cells

Investigators from across the globe report promising interim safety and efficacy data from 10 patients who received an investigational gene-editing based therapy, CTX001. The trials are the first to test a CRISPR-Cas9 gene editing therapy in humans for a genetic disease, researchers reported.

Sickle cell disease (SCD) can cause a variety of health problems including episodes of severe pain, called vaso-occlusive crises, as well as organ damage and strokes. Patients with transfusion-dependent thalassemia are dependent on blood transfusions from early childhood. The only available cure for both diseases is a bone marrow transplant from a closely related donor, an option that is not available for the vast majority of patients because of difficulty locating matched donors, the cost, and the risk of complications.

In the studies, the researchers’ goal is to functionally cure the blood disorders using CRISPR/Cas9 gene-editing by increasing the production of fetal hemoglobin, which produces normal, healthy red blood cells as opposed to the misshapen cells produced by faulty hemoglobin in the bodies of individuals with the disorders.

The clinical trials involve collecting stem cells from the patients. Researchers edit the stem cells using CRISPR-Cas9 and infuse the gene-modified cells into the patients. Patients remain in the hospital for approximately one month following the infusion.

Prior to receiving their modified cells, the seven patients with beta thalassemia required blood transfusions approximately every three to four weeks and the three patients with SCD suffered episodes of severe pain roughly every other month. All the individuals with beta thalassemia have been transfusion independent since receiving the treatment, a period ranging between two and 18 months. Similarly, none of the individuals with SCD have experienced vaso-occlusive crises since CTX001 infusion. All patients showed a substantial and sustained increase in the production of fetal hemoglobin.

Researchers report that the safety of CTX001 infusion was generally consistent with the chemotherapy regimen received prior to cell infusion. Four serious adverse events related or possibly related to CTX001 were reported in one patient with thalassemia: headache, haemophagocytic lymphohistiocytosis (HLH), acute respiratory distress syndrome, and idiopathic pneumonia syndrome. The patients have now recovered.

“There is a great need to find new therapies for beta thalassemia and sickle cell disease,” said Haydar Frangoul, MD, Medical Director of Pediatric Hematology and Oncology at Sarah Cannon Research Institute, HCA Healthcare’s TriStar Centennial Medical Center. “What we have been able to do through this study is a tremendous achievement. By gene editing the patient’s own stem cells we may have the potential to make this therapy an option for many patients facing these blood diseases.”

Because of the precise way CRISPR-Cas9 gene editing works, Dr. Frangoul suggested the technique could potentially cure or ameliorate a variety of diseases that have genetic origins. 

The trial was sponsored by CRISPR Therapeutics and Vertex Pharmaceuticals.

Haydar Frangoul, MD, The Children’s Hospital at TriStar Centennial and Sarah Cannon Research Institute, will present this study in a plenary presentation on Sunday, December 6, at 7:00a.m. Pacific time on the ASH annual meeting virtual platform. The study will be simultaneously published in the New England Journal of Medicine at the time of the press briefing presentation.

CAR T-Cell Therapy Shows Promise Against High-Risk Non-Hodgkin Lymphoma
700: Primary Analysis of Zuma-5: A Phase 2 Study of Axicabtagene Ciloleucel (Axi-Cel) in Patients with Relapsed/Refractory (R/R) Indolent Non-Hodgkin Lymphoma (iNHL)

The cellular immunotherapy axicabtagene ciloleucel (axi-cel) has dramatically improved the outlook for patients with large B cell lymphoma. In a phase II clinical trial, this therapy brought considerable benefits to patients with non-Hodgkin lymphomas, reducing cancer cells to undetectable levels in nearly 80% of study participants. While non-Hodgkin lymphomas are generally slower growing and less aggressive than large B cell lymphoma, the results suggest axi-cel may be a promising option for patients who have a history of relapse or a lack of response to available therapies. 

“We were very impressed with the magnitude of the responses, and also the durability,” said senior study author Caron Jacobson, MD, of Dana-Farber Cancer Institute. “This treatment has meaningfully affected high-risk patients with these diseases. I was also struck early on by how favorable the safety profile was compared to what we’ve been seeing in the fast-growing lymphomas such as large B cell lymphoma.”

When undergoing axi-cel therapy, a patient’s T cells are removed and genetically altered to express a receptor that seeks and destroys cancer cells. The engineered cells, called chimeric antigen receptor T cells (CAR T cells), are then re-infused into the patient. In previous trials for large B cell lymphoma, the therapy has been shown to reduce cancer cells below detectable levels, described as a complete response, in a substantial portion of patients.

To test the therapy for treating indolent B-cell non-Hodgkin lymphoma, the researchers administered axi-cel to 146 patients with either follicular lymphoma (FL) or marginal zone lymphoma (MZL) at multiple U.S. medical centers. Before the trial, the patients all had continuing lymphoma despite undergoing multiple previous treatments.

Researchers tracked patients for a median of nearly 18 months and analyzed efficacy outcomes among the 84 patients with FL who had at least 12 months of follow-up, and the 20 patients with MZL who had at least one month of follow-up. Overall, 92% of participants achieved an objective response to the treatment and 78% achieved a complete response. By 12 months after their infusion, 72% were still in response. After 17.5 months, 64% were still in response.

All 146 treated patients were analyzed for safety. Almost all patients experienced adverse events, with 86% experiencing adverse events of grade 3 or higher. Seven percent experienced grade 3 or higher cytokine release syndrome, and 19% experienced grade 3 or higher neurologic events. Response rates were slightly higher, and rates of adverse events were slightly lower among patients with FL compared to those with MZL, trends that Dr. Jacobson said may be further illuminated after data become available for a larger number of patients with MZL.

Caron Jacobson, MD, Dana-Farber Cancer Institute, will present this study in an oral presentation on Monday, December 7, at 1:30 p.m. Pacific time on the ASH annual meeting virtual platform.

Study Suggests Opportunity to Personalize Immunotherapy for Patients with Large B Cell Lymphoma
556: CD58 Aberrations Limit Durable Responses to CD19 CAR in Large B Cell Lymphoma Patients Treated with Axicabtagene Ciloleucel but Can be Overcome through Novel CAR Engineering

While the immunotherapy axi-cel has revolutionized treatment for large B cell lymphoma, it does not work for everyone. In a new study, researchers uncovered a likely explanation for why about one-quarter of patients do not respond well to this therapy. The researchers used this information to create a modified version of the treatment that may overcome the problem and make the therapy effective for more patients. 

Axi-cel achieves a complete and lasting response in about 40-50% of patients treated. The treatment involves removing a patient’s T cells and engineering them to express a certain receptor. These engineered cells, called CAR T cells, are then re-infused into the patient, where they use the receptor to seek and destroy cancer cells.

The new study focuses on the role of a protein called CD58 in this process. Analyzing genetic samples from 51 patients treated with axi-cel, the researchers discovered that the tumors of about 25% of the patients lacked a fully functioning version of this protein. In all but one of these patients, the therapy had no lasting effect. The researchers then created a mouse model that lacked CD58 and tested three different CAR-T therapies in the mice. None worked.

Probing the biological mechanisms further, the researchers determined that CD58 helps activate the engineered T cells and assists with the process of killing cancer cells. Without a functional CD58 protein, CAR T cells are less effective. To overcome this problem, the researchers altered the engineering process by adding another protein, called CD2, to fill the role of CD58. Experiments in mice suggest these modified CAR T cells are capable of functioning well without CD58 present.

The researchers said they believe the approach could lead to clinical trials in the next one to two years. If successful, the modified treatment could significantly expand the pool of patients who are likely to benefit from axi-cel therapy.

“Achieving an uptick of 20-25% in the complete response rate would really bring cures to a large number of additional patients,” said senior study author Robbie G. Majzner, MD, of Stanford University School of Medicine. “Ultimately, we could potentially screen patients for CD58 status and provide a more precision approach to this therapy.”

In addition to leading to a next-generation therapy for large B cell lymphoma, the work could have relevance for immunotherapy research more broadly. “CD58 is an emerging biomarker,” said Dr. Majzner. “Endowing immunotherapeutics with the ability to get around CD58 loss may emerge as important for other cancers, as well.”

Robbie G. Majzner, MD, Stanford University School of Medicine, will present this study in an oral presentation on Monday, December 7, at 7:30 a.m. Pacific time on the ASH annual meeting virtual platform.

Additional press briefings will take place throughout the meeting on health disparities, practice-changing clinical trials, COVID-19, and late-breaking abstracts. For the complete annual meeting program and abstracts, visit Follow ASH and #ASH20 on Twitter, Instagram, LinkedIn, and Facebook for the most up-to-date information about the 2020 ASH Annual Meeting.

The American Society of Hematology (ASH) ( is the world’s largest professional society of hematologists dedicated to furthering the understanding, diagnosis, treatment, and prevention of disorders affecting the blood. For more than 60 years, the Society has led the development of hematology as a discipline by promoting research, patient care, education, training, and advocacy in hematology. ASH publishes Blood (, the most cited peer-reviewed publication in the field, and Blood Advances (, an online, peer-reviewed open-access journal.

SOURCE American Society of Hematology

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