Michael had suffered from mysterious medical symptoms his entire life. He received a life-changing treatment following a genetic diagnosis through the Garvan-led CIRCA program.
A genetic diagnosis led to the successful treatment of a 52-year old man, guiding immune therapy for his rare cancer and providing relief after a lifetime of unexplained immune symptoms.
Researchers led by A/Prof Tri Phan at the Garvan Institute of Medical Research, analysed the genome of Sydney man Michael, to discover his symptoms were caused by a variant in an immune gene that also revealed an existing medication to be an effective treatment.
By administering a common immunosuppressant drug used to prevent organ rejection, A/Prof Phan was able to rebalance Michael’s immune system and treat his Kaposi’s sarcoma, a rare cancer which affects the lymph tissues in some people with compromised immune systems. The treatment also improved a number of other symptoms that had affected him all his life.
“Patients like Michael often suffer from long diagnostic odysseys as their conditions are very rare and difficult to diagnose without access to a multidisciplinary team of dedicated doctors and scientists. We were fortunate we were able to solve his case,” says A/Prof Phan, who heads the Intravital Microscopy and Gene Expression Lab at Garvan.
“There is significant potential for genomic studies of patients with primary immunodeficiency diseases like Michael to teach us more about how we can harness the immune system to fight cancer.”
A report of the scientific discoveries that led to the remarkable diagnosis and resulting treatment was published in the .
Unexplained symptoms
Michael was first referred to A/Prof Phan’s clinic in 2015 by his immunologist through the Clinical Immunogenomics Research Consortium Australasia () program.
Michael had severe childhood asthma and a long-standing history of chronic fatigue, which began in his mid-teens and progressively worsened over four decades, cognitive dysfunction, gastrointestinal symptoms, and joint pain. A year earlier, he had developed classic Kaposi’s sarcoma, a rare cancer of the lymphatic cells, which had initially been treated successfully with chemotherapy, but which had since relapsed and was not responding to chemotherapy.
“We suspected his broad spectrum of symptoms might be due to abnormalities in his immune system,” says A/Prof Phan. “His blood tests revealed an unusual immune cell profile I’d only ever seen once before in a patient with a rare genetic immunodeficiency.”
One variant in millions
As the researchers suspected the immune disorder to be genetic, they conducted whole genome sequencing on a blood sample. However the results initially didn’t indicate an obvious cause.
“In order for whole genome sequencing to point to a harmful genetic variant, that variant has to have already been reported in the scientific literature before,” says A/Prof Phan. “As this was not the case with Michael, the challenge was to find which variant was responsible – amongst the many millions of genetic variants that exist between any two people.”
One variant that did stand out as a possible cause was one that had not been reported as significant before, in the CTLA4 gene. CTLA4 is an immune checkpoint protein that ‘puts the brakes’ on the immune system. Using RNA sequencing and functional genomics studies, the researchers established that Michael’s variant resulted in ‘cryptic splicing’ of the CTLA4 gene, leading to an abnormal CTLA4 protein that is not able to dock to its targets and perform its function.
“In Michael’s case, the CTLA4 ‘brake’ wasn’t working – the immune system was overshooting and overworking, resulting in ‘exhaustion’ of immune cells and an immunodeficiency,” says Dr Jin Yan Yap, the first author of the study.
Incidentally, through the CIRCA network, Dr Peter Hsu from the Westmead Children’s Hospital and Dr Lucinda Berglund from Westmead Hospital had also identified an extended family with three patients that had a similar variant causing cryptic splicing of CTLA4. “These cases taken together provided compelling evidence the variant was causing Michael’s immune problems and his rare cancer,” says A/Prof Phan.
The guide to targeted therapy
The diagnosis pointed to a treatment. “We administered a drug called everolimus, an immunosuppressant drug that also boosts immune cells called regulatory T cells. These cells suppress unrestrained activation of conventional T cells and restore the normal function of immune cells. For Michael, we think they restored a normal immune response and recalibrated his anti-cancer immunity,” says A/Prof Phan.
Within a few months, Michael started feeling better and he reported higher levels of energy, a longer attention span and reduction in gastrointestinal symptoms. His cancer is now in remission.
“At that time, Michael was the only person in the world known to have this specific genetic variation and these symptoms, so we were lucky the genetic diagnosis led to a treatment. If it wasn’t for this treatment, his quality of life would have significantly declined,” says A/Prof Phan.
“I have been sick since infancy but as my illness was never validated, I’ve suffered in silence for years. I suspected early on that my symptoms were somehow interlinked. The diagnosis and treatment has given me hope in my life,” says Michael.
“What this study tells you is that the interplay between the immune system and cancer is not black and white,” says A/Prof Phan. “While most immunotherapy is boosting the immune system to target a cancer, in this case, suppressing it allowed it to restore balance.”
