Cancer recurrence may be

stopped with immunotherapy

By Ana Sandoiu | Published Tuesday 17 October 2017

Fact checked by Jasmin Collier

It is common for cancer to unexpectedly recur after a patient

is cleared of the disease. New research sheds light on why
this happens, zooming in on the body's immune system.
The new research was a collaborative
effort among scientists at the Institute of
Cancer Research in London, the Leeds
Institute of Cancer and Pathology, and the
University of Surrey in Guildford all of
which are in the United Kingdom and
researchers from the Mayo Clinic in
Rochester, MN.

The Mayo Clinic's Tim Kottke is the first

author of the study, and the findings have
been published in the journal Cancer
Immunology Research.
T cells are normally able to attack cancer cells (shown here), but
new research finds that residual malignant cells can subvert T cells'
vigilance.

Kottke and his colleagues set out to investigate why cancer recurs after many years of tumor
latency. As the authors explain, understanding and preventing this phenomenon is highly
important because usually, when the cancer recurs, it does so unpredictably and more
aggressively than the first time.

This happens because the cancer becomes resistant to treatment. As the authors
note, knowing how the recurrent tumors differ from the initial ones, as well as what triggers
them, would enable clinicians to intervene in a more timely and effective manner.
How cancer cells subvert the immune cells
To gain a better understanding of these aspects, Kottke and colleagues designed a mouse
model of cancer dormancy.

After treating mice that had cancer with chemotherapy, the rodents seemed cured for
between 40 and 150 days. However, after a longer follow-up period, some of them
"developed late, aggressive local recurrences, mimicking the clinical situation in multiple
tumor types."

After performing several experiments in vivo and in cell cultures, the researchers put this
relapse down to the "subversion" of two main elements of the immune system: the so-called
TNF-alpha chemical, and natural killer (NK) cells.

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First and foremost, they showed that after treatment, the residual cancer cells subverted the
TNF-alpha chemical signal by turning it from an anti-tumor, immune-supporting agent into a
growth factor for the disease.

Secondly, they unraveled the mechanism that weakens the surveillance abilities of both T
cells and NK immune cells.

The scientists found that resistant malignant cells are covered with a large amount of a
molecule called PD-L1, which, in turn, interacts with another molecule called PD-1 on immune
cells, "instructing" the T cells not to attack.

So, Kottke and his team gave the mice a PD-1 or TNF-alpha inhibitor intravenously and
found that "long-term treatment [...] effectively slowed, or prevented, recurrence."

Immunotherapy could 'block' relapse

Study co-author Alan Melcher, a professor of translational immunotherapy at the Institute of
Cancer Research, comments on the findings, saying, "Our study finds the body's own immune
system seems to play a crucial role when cancer relapses."

" The immune system goes from keeping cancer cells in check
to awakening and feeding residual cells, while turning a blind
eye to their growth."
Prof. Alan Melcher

"Excitingly," he continues, "many of the methods employed by treatment-resistant tumors to

regrow and hide from the immune system can be blocked using existing immunotherapies."

"This idea is, in fact, supported by emerging data from clinical trials, showing that
immunotherapies can reduce the risk of cancers coming back," explains Prof. Melcher.

Study co-author Kevin Harrington, who is a professor of biological cancer therapies at the
same institute, also weighs in. "It is becoming [increasingly] clear that the immune system
is at the core of the puzzle of how we can treat cancer more effectively," he says.

"This fascinating new study," adds Prof. Harrington, "helps explain why sometimes a patient's
immune system can be effective against cancer cells while at other times it is not."

"Changes must occur in these [cancer] cells that make them better able to manipulate the
immune system and understanding this could open up new treatment options to prevent
relapse," Prof. Harrington concludes.

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