An aggressive cancer that has spent decades perfecting the art of hiding from the immune system may finally have met its match.
Researchers at the Walter and Eliza Hall Institute have identified a previously overlooked type of immune cell that can recognise and kill small cell lung cancer (SCLC), the deadliest form of the disease, which claims most of its patients within five years of diagnosis.
Published in Cancer Cell, the study found patients whose tumours carried more of these specialised cells lived longer and responded better to treatment, revealing a hidden immune defence that could be harnessed against a cancer that has seen little therapeutic progress in decades.
The cells are gamma delta T cells, a less-familiar branch of the immune system that operates independently of the conventional T cells on which most modern immunotherapies rely. That distinction matters: while immunotherapy has transformed outcomes across many cancers, only a rare subset of SCLC patients experience lasting benefit, largely because these tumours are often invisible to the immune cells those treatments recruit. The new research suggests gamma delta T cells can bypass that invisibility.
"For decades, we've known that small cell lung cancer is exceptionally good at hiding from the immune system," said Professor Kate Sutherland, senior author on the paper and head of the WEHI laboratory. "We've found an immune cell that appears to be able to see through that disguise."
The discovery traces back to data rather than the laboratory bench. The team analysed outcomes from two practice-changing clinical trials, IMpower133 and CASPIAN, which together established immunotherapy as standard care for SCLC, and linked a strong gamma delta T cell signature to the patients who derived the greatest benefit.
"Strikingly, patients whose tumours contained more of these specialised immune cells often had better treatment outcomes," Professor Sutherland said. "This is the strongest evidence yet that gamma delta T cells are present in small cell lung cancers and appear capable of fighting the disease."
To test whether that link was causal, the researchers built miniature versions of patients' tumours in the laboratory, using samples donated through the Victorian Cancer Biobank in collaboration with the Royal Melbourne Hospital. When gamma delta T cells were drawn from patients' own blood and combined with the mini tumours, they proved highly effective at recognising and killing the cancer cells.
The researchers then tested whether two existing drugs could amplify that effect. Zoledronate, approved for osteoporosis and cancer-related bone disease, increased the number of gamma delta T cells available and sharpened their ability to detect the tumours. Tarlatamab, already approved for SCLC, acted like a magnetic force drawing the immune cells into closer contact with the cancer. Together, the drugs significantly enhanced the cells' cancer-killing capacity in the laboratory, pointing to a possible route for strengthening anti-cancer immunity in a disease where options are limited.
The findings also raise the prospect of adoptive cell transfer: growing large numbers of a patient's gamma delta T cells outside the body and infusing them back in. First author Dr Jin Ng noted that therapies expanding and reinfusing these cells already exist, which could accelerate translation.
"For patients with lower gamma delta T cell levels, therapies such as zoledronate may offer a way to boost their cancer-fighting immune cells and responsiveness to treatments," Dr Ng said. "As therapies that expand and reinfuse gamma delta T cells already exist, our findings raise the exciting possibility of rapidly translating this discovery into new treatment strategies."
"This could open an entirely new avenue for personalised treatment approaches in small cell lung cancer and other solid cancers that are often missed by conventional immune cells."
The team now hopes to clinically translate the findings into a new class of immunotherapy drugs for small cell lung cancer, in an ongoing collaboration with researchers at the Doherty Institute. The research was supported by Cancer Council Victoria, the National Health and Medical Research Council, The CASS Foundation and the International Association for the Study of Lung Cancer.
