A new type of immunotherapy that is directed to aggressive blood cancers shows promising results along with manageable side effects, according to the results of an international clinical trial of phase 1/2 directed by researchers at the Faculty of Medicine of the University of Washington in St. Louis.
The clinical trial evaluated the safety and efficacy of an innovative CAR-T cell immunotherapy that is specifically designed to attack cancer T cells. The trial participants had been diagnosed with rare cancers (acute lymphoblastic leukemia of T cell or lymphoblastic lymphoma of T cells) and had run out of treatment options after standard therapy was ineffective for them. With the new immunotherapy, most patients in the study who received the complete dose of the cells achieved the complete remission of their cancer.
The results of the essay were published on May 30 in the magazine Blood.
“For patients with these rare and aggressive cancers, who do not have other options, this has the potential to become a transformative advance in the field,” said principal author John F. Dipersio, MD, PHD, Virginia E. and Sam J. Golman, Professor of Medicine at Washu Medicine, who first developed the therapy in his laboratory in Washu Medicine. “The trial demonstrated a high probability of response to therapy and even remission. This car-t cell treatment is promising to become a” bridge to transplant “therapy for patients who would otherwise be eligible for stem cell transplant, which is the only potentially healing treatment for these blood cancers.”
Larger studies are needed with more patients and longer follow -up before researchers can determine if this new therapy could be healing alone.
The current essay included 28 adults and adolescents with acute Tymphoblastic leukemia of T cells and lymphoblastic T lymphoma of T cells that returned after several therapy lines or never responded to treatment. Around 1,000 people are diagnosed with these types of cancer annually in the US. If cancer does not respond to treatment or returns after the initial treatment, patients survive only six months, on average and less than 7% still live in the five -year brand.
The therapy, called WU-CART-007, was developed by Wugen, a Biotechnology Start Company of Washu founded by Dipersio and other Washu Medicine researchers, including Matthew Cooper, PHD, which co-founded the company when it was in the Washu Medical Faculty and now serves as the main scientific officer of Wugen. The researchers worked with the Washu Technology Management Office (OTM) to launch the company in 2018. The clinical trial was held in Australia, Europe and multiple sites in the United States for the St. Louis site, the essay was carried out in Siteman Cancer Center, based in Barnes-Jewish Hospital and Washu Medicine.
The test design included a dose scale phase, which determined the recommended dose of therapeutic cells that patients would receive for the second phase of the test. Dose climbing helps determine the largest dose of CAR-T cells that patients can receive and still have manageable side effects. Thirteen patients received the complete dose of 900 million CAR-T cells after undergoing a procedure to eliminate patient immune cells themselves. This procedure, called Lymphodeplection, reduces immune cells, which makes the new therapeutic T cells establish and expand in number. Two of these patients died of their cancer or treatment complications, such as infection, during the study period.
Of 11 patients who could be evaluated after treatment, the general response rate was 91%, which means that 10 patients did not show signs of cancer after treatment or their cellular cancer was significantly reduced. Eight of 11 patients (72.7%) reached complete remission. In the studio data cut, six that underwent a transplant remain in the remission, without evidence of illness, from six to 12 months later.
“These response and remission rates, ranging from 70% -90% of patients, are much higher than we would expect from the care standard for this type of cancer, which generally leads to the remission in just 20% -40% of patients,” said the corresponding author and the corresponding author Armin Ghobadi, MD, medical and clinical professor of the director of the Center for the Center of Gender and Cell Washu Medicine. “These answers are notable because the patients in this trial had run out of options. They had very aggressive cancers that returned after several therapy lines, including several that relapsed after an previous stem cell transplant.”
The majority of patients (88.5%) experienced cytokine release syndrome as a side effect of immunotherapy, and these cases were predominantly mild or moderate. Citocine liberation syndrome is a common side effect of CAR-T cell therapy that occurs when a large number of immune cells release chemicals that cause an inflammatory response of full body. About 19% of patients experienced a more severe cytokine release syndrome. A small number of patients experienced more rare side effects, such as neurotoxicity syndrome and low -grade host graft disease. Adverse events were managed with additional therapies.
Cellular therapy
Immunotherapy evaluated in the trial is considered a “universal” car-t cell therapy because, taking advantage of CRISPR gene editing technology, it can occur from cells donated by any healthy individual and used to treat any patient with a T-cell cancer. In contrast, approved Lo-T cell therapies are adapted from the patient’s immune cells. The cells should be collected from the patient and sent to a manufacturing installation to be performed and then sent backwards, a process that generally takes three to six weeks. On the contrary, universal car-t cell therapies can be done in advance, stored frozen and easily available “Light the-Shelf”, largely reducing the waiting time before therapy can begin.
Using CRISPR gene editing tools, the production process eliminates the T cell receptor from donor cells, largely reducing the risk of graft disease against host, in which donor T cells attack healthy tissue. Eliminating another key antigen also prevents car-T cells from attacked with each other. The types of rare cancers in this study presented a unique challenge: therapeutic cells and cancer cells are T cells, so measures should be taken to prevent therapeutic T cells from confusing with each other with cancer and cause fraratricide of car-t cells. All other approved car-t cell therapies are directed to B cell cancers, which do not have this self-objective complication of T cells. After using the CRISPR gene edition to modify the CAR-T cells to prevent these harmful side effects, the cells are designed even more to sign up for a protein called CD7 on the surface of the cancer T cells and then destroy cancer.
“A larger international clinical trial of this therapy is already underway,” said Dipersio. “We must first complete this largest trial, but we hope that this universal car-t cell therapy can become an approved treatment for patients with mortal T cell cancers.”