Investigating cancer drug toxicity leads to a critical discovery
Researchers uncover a new strategy to avoid cancer immunotherapy side
effects

Date:
May 4, 2022
Source:
La Jolla Institute for Immunology
Summary:
When patients started showing adverse side effects during a cancer
immunotherapy trial, researchers went back through the data and
worked with patient samples to see what went wrong.



FULL STORY ==========================================================================
It's not often that a failed clinical trial leads to a scientific
breakthrough.


==========================================================================
When patients in the UK started showing adverse side effects during
a cancer immunotherapy trial, researchers at La Jolla Institute for
Immunology (LJI) Center for Cancer Immunotherapy and University of
Liverpool went back through the data and worked with patient samples to
see what went wrong.

Their findings, published recently in Nature, provide critical clues to
why many immunotherapies trigger dangerous side effects -- and point to
a better strategy for treating patients with solid tumors.

"This work shows the importance of learning from early stage clinical
trials," says La Jolla Institute for Immunology (LJI) Professor
Pandurangan Vijayanand, M.D., Ph.D., who co-led the new research with
Christian H. Ottensmeier, M.D., Ph.D., FRCP, a professor with the
University of Liverpool, The Clatterbridge Cancer Centre NHS Foundation
Trust, and adjunct professor at LJI.

Limited success with immunotherapies Both Vijayanand and Ottensmeier
are physician scientists, and Ottensmeier is an attending oncologist
who treats solid tumor patients. In just the last decade, he has seen
more and more patients thrive thanks to advances in immunotherapies,
which work with the immune system to kill cancers.



==========================================================================
"In the oncology world, immunotherapy has revolutionized the way we
think about treatment," says Ottensmeier. "We can give immunotherapies to patients even with metastatic and spreading disease, and then just three
years later wave goodbye and tell them their cancer is cured. This is an astounding change." Unfortunately, only around 20 to 30 percent of solid cancer patients given immunotherapies go into long-term remission. Some
people see no change after immunotherapy, but others develop serious
problems in their lungs, bowel, and even skin during treatment. These
side effects can be debilitating, even fatal, and these patients are
forced to stop receiving the immunotherapy.

Important lessons from a clinical trial The researchers at LJI and the University of Liverpool worked with samples from a recent clinical trial
in the UK for patients with head and neck cancers. The patients were
given an oral cancer immunotherapy called a PI3Kd inhibitor. At the time,
PI3Kd inhibitors had proven effective for B cell lymphomas but had not
yet been tested in solid tumors.

PI3Kd inhibitors are new to the cancer immunotherapy scene, but
they hold promise for their ability to inhibit "regulatory" T cells
(Tregs). Tregs normally try to stop other T cells, called effector
T cells, from targeting the body's own tissues. Oncologists inhibit
Tregs inside tumors so effector T cells can let loose and generate cancer-killing CD8+ T cells.



========================================================================== "Having an oral tablet that can take off the brakes -- the Tregs --
can be a great asset for oncologists," says Vijayanand.

Unfortunately, 12 of the 21 patients in the trial had to discontinue
treatment early because they developed inflammation in the colon,
a condition called colitis. "We thought this drug wouldn't be toxic,
so why was this happening?" says Vijayanand.

LJI Instructor Simon Eschweiler, Ph.D., spearheaded the effort to go back
and see exactly how PI3Kd inhibitor treatment affected immune cells in
these patients. Using single-cell genomic sequencing, he showed that in
the process of increasing tumor-fighting T cells in tumors, the PI3Kd inhibitor, also blocked a specific Treg cell subset from protecting the
colon. Without Tregs on the job, pathogenic T cells, called Th17 and
Tc17 cells, moved in and caused inflammation and colitis.

It was clear that the cancer trial patients had been given a larger
PI3Kd inhibitor dose than they needed, and the immunotherapy had thrown
the delicate composition of immune cells in the gut out of balance.

The pathway that leads to the toxicity seen in the new study may
be broadly applicable to other organs harboring similar Treg cells,
and to other Treg cell-targeting immunotherapies like anti-CTLA-4,
Eschweiler says.

New dosing strategy may save lives The team found that intermittent dosing could be a valid treatment strategy that combines sustained anti-tumor
immunity with reduced toxicity.

The researchers are now designing a human clinical trial to test the intermittent dosing strategy in humans.

"This research illustrates how you can go from a clinical study to
a mouse study to see what's behind toxicity in these patients," says
LJI Professor and Chief Scientific Officer Mitchell Kronenberg, Ph.D.,
whose lab led much of the mouse model work for the new study.

How to explain lack of toxicity in trials for B cell lymphomas? Eschweiler
says lymphoma patients in previous studies had been given several prior therapies leading to an overall immunocompromised state. This means the lymphoma patients didn't have the same type -- or the same magnitude
-- of immune response upon PI3Kd inhibition. Meanwhile, the head and
neck cancer patients were treatment- naive. Their immune system wasn't compromised, so the immune-related adverse events were both more rapid
and more pronounced.

Overall, the new study shows the importance of studying not just
personalized therapies but personalized therapy doses and schedules.

As Ottensmeier explains, doctors ten years ago only had one type of immunotherapy to offer. It either helped a patient or it didn't. Doctors
today have a rapidly growing library of immunotherapies to choose from.

Vijayanand and Ottensmeier are among the first researchers to use
single-cell genomic sequencing tools to determine which therapeutic combinations are most effective in individual patients -- and the best
timeline for giving these therapies. In a 2021 Nature Immunology study,
the pair showed the potential importance of giving immunotherapies in
a specific sequence.

"If you design your clinical trials well and apply sophisticated genomics,
you have a lot to learn," says Vijayanand. "You can figure out what's
happening and go back to the patients."

========================================================================== Story Source: Materials provided by
La_Jolla_Institute_for_Immunology. Original written by Madeline McCurry-Schmidt. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Eschweiler, S., Rami'rez-Sua'stegui, C., Li, Y. et al. Intermittent
PI3Kd
inhibition sustains anti-tumour immunity and curbs irAEs. Nature,
2022 DOI: 10.1038/s41586-022-04685-2 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/05/220504110410.htm

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