News & numbers
Rectal cancer breakthrough "There’s a high level of investment in people, quality and safety monitoring,
and the effort to dive deeper into the science.” Ken Mills, CEO of Regenxbio, on the growing momentum to bring cell and gene therapies to market
A new study on the effects of an immunoablative therapeutic, named dostarlimab, has resulted in a 100% remission rate for patients with rectal cancer. The participants chosen for the study had mismatch repair deficient (MMRd) locally advanced rectal cancer – a molecular sub type of the disease that makes tumours resistant to chemotherapy. The first line of treatment for localised colon cancer tends to be surgical, with chemotherapy given after (called adjuvant chemotherapy) to kill any cancer cells left behind. But with the findings from this study, conducted at Memorial Sloan Kettering Cancer Center (MSK), researchers believe immunoablative therapy could replace surgery, chemotherapy and radiation. “Surgery and radiation have permanent effects on fertility, sexual health, bowel and bladder function. The implications for quality of life are substantial, especially in those where standard treatment would impact childbearing potential. As the incidence of rectal cancer is rising in young adults, this approach can have a major impact,” said co-leader of the study, MSK’s Dr Andrea Cercek, MD, section head of Colorectal Cancer and co-director of the Center for Young Onset Colorectal and Gastrointestinal Cancer.
The MSK researchers conducted a prospective study in which the single agent dostarlimab, an anti-PD-1 monoclonal antibody, was administered every three weeks for six months in patients with mismatch repair- deficient stage two and three rectal adenocarcinoma, to be followed by standard chemoradiation and surgery. Patients who achieved a clinical complete response were eligible for omission of chemoradiation and surgery. The 14 participants treated with dostarlimab achieved a clinical complete response with no evidence of tumour on MRI, FDG-PET, endoscopic visualisation,
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digital rectal exam, or biopsy, which satisfied the study’s co-primary endpoint. To date, no patients have required chemoradiation or surgery, and no cases of progression or recurrence have been noted during up to 25 months of follow- up examinations.
“Since MMRd colorectal cancer is responsive to PD-1 blockade in the metastatic setting, we hypothesised that locally advanced mismatch repair-deficient rectal cancer is sensitive to checkpoint blockade and may alter the requirements for chemoradiotherapy and surgery, or eliminate the need for additional treatments altogether,” said Cercek. “The immunotherapy shrank the tumours much faster than expected,” Cercek confirmed. “Patients came into my office after just two or three treatments and said, ‘This is incredible. I feel normal again.’”
Despite the impressive results of the
study, approximately 5–10% of rectal cancers are molecularly characterised as being deficient in mismatch repair enzymes, making them eligible for treatment with dostarlimab. But on top of this, the small sample size of 14 patients limits the generalisability of the trial results. Hanna K. Sanoff, MD, MPH, medical oncologist and associate professor, Department of Medicine, University of North Carolina, said: “These initial findings of the remarkable benefit with the use of dostarlimab are very encouraging but also need to be viewed with caution until the results can be replicated in a larger and more diverse population.
“The responses in these first 12 of a planned-for 30 patients in the trial were remarkable and exceed what we would expect with the standard chemotherapy plus radiation.
"Although quality of life measures have not been reported yet, it’s encouraging that some of the most difficult symptoms, such as pain and bleeding, all resolved with the use of dostarlimab.”
7%
The percentage of the 340 FDA- approved biologics that are designated as cell and gene therapies. FDA and Evaluate Pharma
Boosted CAR-T cells
An immunity-boosting protein called Interleukin 7 (IL-7) could be effective at improving CAR-T cell therapy for cancer patients, according to a new study. The researchers found that after an infusion of genetically modified IL-7 – a type of T cell – the cancer-fighting CAR-T cells grew in number and became more effective at killing tumour cells in a mouse model. The study, conducted by Washington University School of Medicine in St. Louis, suggests promise for a phase 1 clinical trial investigating a long-acting genetically modified type of IL-7 in conjunction with CAR-T cells targeting CD19 – a B cell antigen in patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL). “Many researchers are trying different strategies to enhance the function of CAR-T cells in treating blood cancers,” said senior author John F. DiPersio, MD, PhD, the Virginia E. and Sam J. Golman, Professor of Medicine and director of the Division of Oncology. “We’re interested in IL-7 because we know it is a major driver of T cell expansion. The body makes IL-7 naturally to ramp up the number of T cells when a person gets sick, for example. When we give a long-acting type of IL-7 to tumour- bearing immunodeficient mice soon after CAR-T cell treatment, we see a dramatic expansion of these CAR-T cells greater than ten-thousandfold when compared with mice not receiving IL-7.
“These CAR-T cells also persist longer and show dramatically increased anti- tumour activity.”
While natural IL-7 disappears quickly from the body, the modified version used in the study was adapted to circulate in the body for weeks. The phase 1 trial will be coordinated by Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine in St. Louis, with three other sites participating.
Clinical Trials Insight /
www.worldpharmaceuticals.net
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