"Nature" accident!

When patients in the UK started experiencing adverse side effects in a cancer immunotherapy trial, researchers from the La Jolla Institute for Immunology (LJI) Cancer Immunotherapy Centre and the University of Liverpool reviewed data and studied patient samples to determine Find out what's wrong

Their findings, recently published in the journal Nature, provide key clues to why many immunotherapies cause dangerous side effects and lead to better strategies for treating patients with solid tumors

"This work shows the importance of learning from early clinical trials," said Professor Pandurangan Vijayanand from the La Jolla Institute for Immunology (LJI)

Immunotherapy with limited success

Both Vijayanand and Ottensmeier are internal medicine scientists, and Ottensmeier is an attending oncologist who treats patients with solid tumors

"In oncology, immunotherapy has revolutionized the way we think about treatment," Ottensmeier said

Unfortunately, only about 20 to 30 percent of solid cancer patients receive long-term remission after immunotherapy

Important lessons from clinical trials

The LJI and University of Liverpool researchers used samples from a recent clinical trial of head and neck cancer patients in the UK

PI3Kδ inhibitors are new drugs in the field of cancer immunotherapy, but they have the ability to suppress "regulatory" T cells (Treg)

"Having an oral tablet that relieves Treg symptoms is a huge asset for oncologists," Vijayanand said

Unfortunately, 12 of the 21 patients in the trial had to stop treatment early due to developing inflammation of the colon (colitis)

LJI instructor Dr.

Clearly, cancer trial patients were given larger doses of the PI3Kδ inhibitor than they needed, and the immunotherapy unbalanced the delicate makeup of immune cells in the gut

The pathways that lead to toxicity identified in the new study may be broadly applicable to other organs that harbor similar Treg cells, as well as other immunotherapies that target Treg cells, such as anti-CTLA-4, Eschweiler said

New drug strategy may save lives

The team found that intermittent dosing may be an effective therapeutic strategy that combines sustained antitumor immunity with reduced toxicity

The researchers are currently designing a human clinical trial to test this intermittent dosing strategy in humans

"This study illustrates how to go from clinical studies to mouse studies to understand what's behind the toxicity in these patients," said LJI professor and chief scientific officer Mitchell Kronenberg, Ph.

How could the lack of toxicity in the B-cell lymphoma trial be explained? In previous studies, patients with lymphoma had been treated several times, leading to overall immunocompromise, Eschweiler said

Overall, the new study shows that it is not just personalised therapy to be studied, but also the dose and schedule of personalised therapy
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A decade ago, doctors could only offer one type of immunotherapy, Ottensmeier explained
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Either it helps the patient or it doesn't
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Doctors today have a rapidly growing arsenal of immunotherapies to choose from
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Vijayanand and Ottensmeier are among the first researchers to use single-cell genome sequencing tools to determine which treatment combinations are most effective for individual patients, and the optimal schedule for administering those treatments
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In a 2021 study in Nature Immunology, the pair showed the potential importance of delivering immunotherapy in a specific order
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"If you design your clinical trials and apply complex genomics, you still have a lot to learn," Vijayanand said.
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You can figure out what's going on and get back to the patient
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"

Intermittent PI3Kδ inhibition sustains anti-tumour immunity and curbs irAEs .
Nature