SickKids-led research uncovers potential immune-based therapy for difficult to treat childhood cancers
New research led by scientists at The Hospital for Sick Children (SickKids) has uncovered the biological traits of certain inherited childhood cancers, showing that a treatment option that was previously disregarded may have clinical benefit for many patients, as understanding has evolved about cancer response to immunotherapy. The International Replication Repair Deficiency Consortium – an international consortium of patients, clinicians and researchers from more than 45 countries across four continents – looked at cancers caused by DNA replication errors, characterized by mismatch-repair deficiency (MMRD) and polymerase-proofreading deficiency (PPD). These types of cancer are often fatal due to an inherent resistance to common cancer treatments, including many chemotherapy agents, and almost always relapse after radiation therapy.
Previous research had shown that a type of immunotherapy called immune checkpoint inhibitors (ICI) showed little benefit to children with cancers. However, in a study published in Nature Medicine on January 6, 2022, a research team led by Dr. Uri Tabori, Staff Physician in Haematology/Oncology and Senior Scientist in the Genetics & Genome Biology program at SickKids, has shown for the first time that the extreme hypermutation that causes resistance to chemotherapy and radiation therapy could be the key to the unique response to immunotherapy in cancers with DNA replication errors.
“Our hypothesis was that cancers that originate from genetic DNA replication errors could actually benefit from immunotherapy because of the sheer number of abnormal variations in the cancer cells,” says Dr. Anirban Das, lead author of the study and Clinical-Research Fellow in Haematology/Oncology and clinician-scientist trainee at the Brain Tumour Research Centre at SickKids.
“We also hypothesized that the unique spectrum of the variations in these cancers could help shed light on the mechanisms of response following immunotherapy. Our data explains why immunotherapy works for these patients, in contrast to the traditional viewpoint that suggested a lack of efficacy in treating other childhood cancers and brain tumours in general.”
Immunotherapy provides ‘remarkable’ improvement in survival for certain childhood cancers
Using data from the International Replication Repair Deficiency Consortium, the SickKids team, including Drs. Tabori, Das, Sumedha Sudhaman, Vanessa Bianchi, Eric Bouffet, Daniel Morgenstern, Cynthia Hawkins and Adam Shlien, examined the immunotherapy treatment of 45 progressive or recurrent tumours from these patients between May 2015 and March 2019. The researchers saw what they describe as remarkable responses to treatment not seen before for some types of childhood cancers which translated to improvements in survival. For example, the researchers saw that up to half of the patients survived for three years, up from little over two and a half months previously reported.
For tumours not found in the brain, Tabori, Principal Investigator of the study, says, “at the time of the study’s publication, all patients who continued the immunotherapy were responding well.”
“These results are very encouraging. These are devastating cancers, and they disproportionally affect children and young adults in developing countries and Indigenous communities.”
High number of cancer cell variations help support positive response to immunotherapy, particularly in young patients
According to the researchers, the positive responses and favourable outcomes that they observed in the inherited childhood replication-repair deficient cancers can be explained by several key biological features that are rooted in the high number of variations in the cancer cell, as well as the young age of the patients. The researchers also saw that the types of variations seen in the cancer cells and the ongoing accumulation of those help these patients to produce an immune response which eventually kills the cancer cells.
Tabori and his research team note that these findings provide valuable insights not only for patients with these certain types of cancer, but also for their family members who may have similar genetic variations. The next step for their research is to complete a clinical trial that avoids radiation and chemotherapy and instead uses immunotherapy as the primary treatment for hereditary cancers caused by DNA replication errors. They are also investigating combination of therapies to improve survival even if immunotherapy alone fails for some of these patients.
This work was supported by Stand Up to Cancer, BioCanRx, Canadian Institutes of Health Research (CIHR), CIHR Joint Canada-Israel Health Research Program, V Foundation for Cancer Research, St. Baldrick’s Foundation with support from Team Campbell, Meagan’s Hug, the SickKids Research Institute’s Clinician Scientist Training Program, LivWise Foundation, Zane Cohen Centre, Brainchild Foundation, Elmaagacli Family Fund, Guglietti We Love You Connie Foundation, Ontario Ministry of Research and Innovation, Canada Research Chair in Childhood Cancer Genomics and SickKids Foundation.