Small cell lung cancer (SCLC) is one of the world’s deadliest diseases, with a five-year survival rate of less than 7%.

While immunotherapy has transformed outcomes for other cancers, only a rare subset of SCLC patients will experience long-term benefits from the treatment.

One major reason is that these cancers are often invisible to the conventional immune cells that immunotherapy treatments rely on, making them difficult to detect and treat.

The new Cancer Cell study reveals a previously unrecognised immune pathway that can override these invisibility powers, unlocking a potential new therapeutic avenue for SCLC patients.

Professor Kate Sutherland, senior author on the paper and WEHI laboratory head, said the findings could help solve one of the field’s most pressing questions: how to boost the number of lung cancer patients who respond to immunotherapy.

“For decades, we’ve known that small cell lung cancer is exceptionally good at hiding from the immune system,” Prof Sutherland said.

“We’ve found an immune cell that appears to be able to see through that disguise.

“Strikingly, patients whose tumours contained more of these specialised immune cells often had better treatment outcomes.

“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.

“It suggests these cells may offer an alternative immune attack route for tumours that are able to evade conventional cancer-fighting immune cells, opening up new possibilities for treating a cancer that has seen few advances over the past decades.”

To test whether gamma delta T cells could fight cancer, researchers created miniature tumours in the lab using samples generously donated by patients through the Victorian Cancer Biobank in collaboration with the Royal Melbourne Hospital. These “mini tumours” represent one of the most realistic laboratory models of SCLC developed to date.

When the team combined the mini tumours with gamma delta T cells taken from the patients’ own blood, they found the immune cells were highly effective at recognising and killing SCLC cells.

The researchers discovered they could amplify this immune response by using two existing drugs – tarlatamab (a cancer treatment approved for SCLC) and zoledronate (approved for osteoporosis and cancer-related bone disease).

The team found zoledronate increased the number of gamma delta T cells available and enhanced their ability to recognise SCLC tumours. Tarlatamab acted like a magnetic force that brought the immune cells into closer contact with the cancer.

Together, these drugs significantly enhanced the gamma delta T cells’ ability to attack the cancer cells, suggesting a potential new way to strengthen anti-cancer immunity in SCLC.

Dr Jin Ng, first author on the paper, said the findings also raise the possibility of using existing gamma delta T cells for adoptive transfer therapies – where large numbers of these immune cells are grown outside the body and infused back into patients.

“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 focused on gamma delta T cells after analysing data from two practice-changing clinical trials – IMpower133 and CASPIAN – which established immunotherapy as a standard treatment for SCLC.

Using advanced genomic and computational analyses led by WEHI’s genomics and bioinformatics teams, researchers were able to link a strong gamma delta T cell signature to patients who experienced the greatest benefit from immunotherapy.

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 is supported by Cancer Council Victoria, the National Health and Medical Research Council (NHMRC), The CASS Foundation, The International Association for the Study of Lung Cancer.

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Header image: A tissue sample taken from a long survivor patient with small cell lung cancer (SCLC), showing gamma delta T cells (red) infiltrating the tumour. WEHI researchers have found these immune cells can recognise and attack SCLC cells (white), revealing a promising new immune pathway for one of the deadliest forms of lung cancer. Other immune cells are shown in green.