A new type of immunotherapy that targets aggressive blood cancers shows promising results alongside manageable side effects, according to the results of an international phase 1/2 clinical trial led by researchers at Washington University School of Medicine in St. Louis.
The clinical trial evaluated the safety and efficacy of an innovative CAR-T cell immunotherapy that is specifically designed to attack cancerous T cells. Participants in the trial had been diagnosed with rare cancers — T cell acute lymphoblastic leukemia or T cell lymphoblastic lymphoma — and had run out of treatment options after standard therapy proved ineffective for them. With the new immunotherapy, most of the patients in the study who received the full dose of cells achieved full remission of their cancer.
The trial’s results were published May 30 in the journal Blood.
“For patients with these rare and aggressive cancers, who have no other options, this has the potential to become a transformative advance in the field,” said senior author John F. DiPersio, MD, PhD, the Virginia E. & Sam J. Golman Professor of Medicine at WashU Medicine, who first developed the therapy in his lab at WashU Medicine. “The trial demonstrated a high likelihood of response to the therapy and even remission. This CAR-T cell treatment shows promise in becoming a ‘bridge-to-transplant’ therapy for patients who would otherwise not be eligible for stem cell transplantation, which is the only potentially curative treatment for these blood cancers.”
Larger studies with more patients and longer follow-up are necessary before the researchers can determine whether this new therapy could be curative on its own.
The current trial included 28 adult and adolescent patients with T cell acute lymphoblastic leukemia and T cell lymphoblastic lymphoma that either returned after several lines of therapy or that never responded to treatment. About 1,000 people are diagnosed with these cancers annually in the U.S. If the cancer does not respond to treatment or returns after initial treatment, patients survive only six months, on average, and less than 7% are still living at the five-year mark.
The therapy, called WU-CART-007, was developed by Wugen, a WashU biotech startup company founded by DiPersio and other WashU Medicine investigators, including Matthew Cooper, PhD, who co-founded the company when he was on the WashU Medicine faculty and now serves as Wugen’s chief scientific officer. The researchers worked with WashU’s Office of Technology Management (OTM) to launch the company in 2018. The clinical trial was conducted in Australia, Europe and multiple sites across the U.S. For the St. Louis site, the trial was conducted at Siteman Cancer Center, based at Barnes-Jewish Hospital and WashU Medicine.
The trial design included a dose-escalation phase, which determined the recommended dose of therapeutic cells that patients would receive for the second phase of the trial. Dose escalation helps determine the largest dose of CAR-T cells that patients can receive and still have manageable side effects. Thirteen patients received the full dose of 900 million CAR-T cells after undergoing a procedure to clear the patients’ own immune cells. This procedure — called lymphodepletion — reduces immune cells, making room for the new therapeutic T cells to establish themselves and expand in number. Two of these patients died from their cancer or treatment complications, such as infection, during the study period.
Of 11 patients who could be evaluated after treatment, the overall response rate was 91%, meaning 10 patients either showed no signs of cancer after treatment or their cancer cell burden was reduced significantly. Eight out of 11 patients (72.7%) achieved complete remission. At the study’s data cut off, six who underwent a transplant remain in remission, with no evidence of disease, six to 12 months later.
“These response and remission rates — ranging from 70%-90% of patients — are much higher than we would expect from standard-of-care for this cancer type, which typically leads to remission in only 20%-40% of patients,” said first and corresponding author Armin Ghobadi, MD, a professor of medicine and clinical director of the Center for Gene and Cellular Immunotherapy at WashU Medicine. “These responses are remarkable because the patients in this trial had run out of options. They had very aggressive cancers return after several lines of therapy, including several who relapsed after an earlier stem cell transplant.”
Most patients (88.5%) experienced cytokine release syndrome as a side effect of the immunotherapy, and these cases were predominantly mild or moderate. Cytokine release syndrome is a common side effect of CAR-T cell therapy that occurs when large numbers of immune cells release chemicals that cause a full-body inflammatory response. About 19% of the patients experienced more-severe cytokine release syndrome. A small number of patients experienced rarer side effects, such as neurotoxicity syndrome and low-grade graft-versus-host disease. Adverse events were managed with additional therapies.
Off-the-shelf cell therapy
The immunotherapy evaluated in the trial is considered a “universal” CAR-T cell therapy because — harnessing CRISPR gene editing technology — it can be produced from cells donated by any healthy individual and used to treat any patient with a T cell cancer. In contrast, approved CAR-T cell therapies are adapted from the patient’s immune cells. The cells must be collected from the patient and shipped to a manufacturing facility to be made and then shipped back, a process that typically takes three to six weeks. In contrast, universal CAR-T cell therapies can be made ahead of time, stored frozen and be readily available “off-the-shelf,” greatly reducing the wait time before therapy can begin.
Using CRISPR gene editing tools, the production process deletes the T cell receptor from the donor cells, greatly reducing the risk of graft-versus-host disease, in which donor T cells attack healthy tissue. Removing another key antigen also prevents the CAR-T cells from attacking one another. The types of rare cancers in this study presented a unique challenge: the therapeutic cells and the cancer cells are both T cells, so steps must be taken to prevent the therapeutic T cells from mistaking one another for the cancer and causing CAR-T cell fratricide. All other approved CAR-T cell therapies target B cell cancers, which do not have this T cell self-targeting complication. After using CRISPR gene editing to modify the CAR-T cells to prevent these harmful side effects, the cells are further engineered to target a protein called CD7 on the surface of cancerous T cells to then destroy the cancer.
“A larger international clinical trial of this therapy is already underway,” DiPersio said. “We must complete this larger trial first, but we are hopeful this universal CAR-T cell therapy can become an approved treatment for patients with deadly T cell cancers.”
A New Hope for Aggressive Blood Cancers: Expert Insights on Universal CAR-T Therapy
Keywords: CAR-T therapy, blood cancer treatment, immunotherapy, T cell acute lymphoblastic leukemia, T cell lymphoblastic lymphoma, clinical trial, CRISPR gene editing, WU-CART-007, off-the-shelf therapy, stem cell transplant, cancer remission
A recent international clinical trial, led by researchers at Washington university School of Medicine in St. Louis, has yielded highly promising results for a new type of immunotherapy targeting aggressive blood cancers. This innovative CAR-T cell therapy, designed to attack cancerous T cells, offers a potential lifeline to patients with T cell acute lymphoblastic leukemia (T-ALL) and T cell lymphoblastic lymphoma (T-LL), who have exhausted other treatment options.
Time.news spoke with Dr. Eleanor Vance,a leading hematologist-oncologist and expert in CAR-T cell therapies,to delve deeper into the implications of this breakthrough and what it means for patients and the future of cancer treatment.
Time.news: Dr. Vance, thank you for joining us. This new CAR-T therapy,WU-CART-007,sounds incredibly promising. Coudl you explain its meaning compared to existing treatments for T-ALL and T-LL?
Dr. Vance: Absolutely. The current standard of care for relapsed or refractory T-ALL and T-LL is often ineffective,leaving patients with a grim prognosis. This trial offers a potential “bridge-to-transplant” therapy, allowing patients to reach a point where they can benefit from a stem cell transplant – often the only curative option. The response rates seen in the trial, with notable remission in a high percentage of patients, are truly remarkable and significantly higher than what we typically observe with conventional treatments.
Time.news: The article highlights that WU-CART-007 is a “universal” or “off-the-shelf” CAR-T therapy. What advantages does this offer over customary CAR-T therapies?
Dr. Vance: That’s a crucial distinction. Traditional CAR-T therapies are personalized, manufactured using a patient’s own immune cells. This process can take several weeks, which is precious time when dealing with aggressive cancers. “Off-the-shelf” CAR-T eliminates this delay. These therapies are pre-made from healthy donor cells, readily available to be administered as soon as a patient is eligible. This drastically reduces the waiting period and could perhaps save lives,as some patients don’t have weeks to wait.
Time.news: The trial utilized CRISPR gene editing technology to develop WU-CART-007. How does this technology contribute to the safety and efficacy of the therapy?
Dr. Vance: CRISPR gene editing is essential in making this therapy viable. In this type of cancer, the CAR-T cells and cancer cells are both T cells, and would, without modification, target each other. CRISPR allows researchers to “edit out” the T cell receptor, reducing the risk of graft-versus-host disease (GVHD) where the donor T cells attack the patient’s healthy tissues. Removing a different antigen also prevents the engineered T cells from attacking one another, a phenomenon called “fratricide.” This precision ensures the CAR-T cells specifically target the cancerous T cells while minimizing harm to the patient.
Time.news: The trial did report some side effects,including cytokine release syndrome (CRS). How manageable are these side effects, and what can patients expect?
Dr. Vance: Cytokine release syndrome is a known side effect of CAR-T therapy, but the majority of cases reported in the trial were mild or moderate and were managed with established protocols. Serious CRS and other side effects like neurotoxicity are, of course, a concern, but these are continuously improving with advances in CAR-T cell therapy management. Patients undergoing this therapy will need close monitoring by a specialized medical team equipped to handle such complications.
Time.news: The article mentions that a larger international clinical trial is already underway. What are the next steps in bringing this therapy to patients who need it?
Dr. Vance: This larger trial is critical.It will allow researchers to gather more data on the long-term efficacy and safety of WU-CART-007 in a broader patient population. It’s also vital to determine if this therapy can eventually be curative on its own, without the need for a stem cell transplant. The data from this expanded trial will inform regulatory approval, paving the way for broader access to this potentially life-saving treatment.
Time.news: For readers who have been diagnosed with T-ALL or T-LL, what practical advice would you offer?
Dr. Vance: first, seek care at a complete cancer center with expertise in blood cancers and CAR-T cell therapy. Discuss all treatment options with your oncologist, including clinical trials like the one mentioned in the article. Staying informed and actively participating in your treatment decisions is crucial. Patient advocacy groups can also be invaluable resources for support and access to information. Remember,while these cancers are aggressive,advances in research like WU-CART-007 are providing new hope for better outcomes.
Time.news: Dr. Vance, thank you again for sharing your expertise. This offers a much clearer perspective on a potentially transformative approach to cancer treatment.
