Boosting T cells improves survival in mice with glioblastoma
Treatment with interleukin-7 revs up immune system against deadly brain
tumor

Date:
January 18, 2022
Source:
Washington University School of Medicine
Summary:
A new study shows that treatment with an immune-boosting protein
called interleukin 7 (IL-7) in combination with radiation improves
survival in mice with glioblastoma. The study in mice suggests
promise for a phase 1/ 2 clinical trial that is investigating a
long-acting type of IL-7 in patients with glioblastoma.



FULL STORY ========================================================================== Glioblastoma, an aggressive cancer in the brain or spinal cord, has
proven stubbornly resistant to newer immunotherapies. And radiation and chemotherapy, the standard treatment for glioblastoma, result in fewer
than 10% of patients surviving longer than five years after diagnosis.


==========================================================================
But a new study from researchers at Washington University School of
Medicine in St. Louis shows that treatment with an immune-boosting
protein called interleukin 7 (IL-7) in combination with radiation improves survival in mice with glioblastoma. The new mouse study shows that IL-7 increases the number of T cells in the tumor and other immune organs. Such immune cells can then attack the cancer cells and improve survival.

The findings are published Jan. 14 in Clinical Cancer Research, a journal
of the American Association for Cancer Research.

The study in mice suggests promise for a phase 1/2 clinical trial at
Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine in St. Louis that is investigating a long-acting type
of IL-7 in patients with glioblastoma.

Radiation in combination with chemotherapy is the standard of care
for various cancers including glioblastoma. Although beneficial
against cancer, these treatments also can impair patients' T cells,
known as lymphocytes, that are important for fighting infections. Many glioblastoma patients have low levels of T cells. Glioblastoma patients
who have chronically low lymphocyte counts don't survive as long as
patients with higher numbers of these T cells.

"Previously, a multicenter study from the American Brain Tumor Consortium showed a six-month shorter survival for patients with low versus normal
numbers of T cells," said first author Jian L. Campian, MD, PhD, who
conducted the research at Washington University School of Medicine and
the Brain Tumor Center at Siteman. "We knew that glioblastoma patients
with low lymphocytes surprisingly also have low IL-7, which is a growth
factor that supports T cells. Normally, people with low T cells should
have a high level of IL-7. We wanted to find out if giving IL-7 to
patients could increase the numbers of T cells and, in the process,
have a positive impact on survival." The researchers found that mice
with glioblastoma tumors treated with a combination of chemotherapy,
radiation and IL-7 lived longer than mice that received only chemotherapy
and radiation. On average, control mice that received no treatment lived
about 20 days after tumor implantation. The mice that received IL-7 alone
lived about 30 days, and those that received radiation alone lived about
35 to 40 days. The mice that received a combination of radiation and
IL-7 lived at least 40 days, and many were still alive at 90 days. The
longest survival was in the mice that received the triple combination of chemotherapy, radiation and IL-7, most of which lived at least 45 days,
with many still alive at the 90-day mark.



========================================================================== "It's difficult to know how these increases in survival in mice might
translate to people," said co-senior author Milan Chheda, MD, an associate professor of medicine. "If many of these mice are surviving at least
three months by adding IL-7, we're hoping to see some type of improvement
in our patients who are treated with IL-7. As a basis for comparison,
the chemotherapy given for glioblastoma is called temozolomide, and it
was first approved because it improved patient survival by an average of slightly over two months." In addition to increasing T cell numbers in
the tumor and the tumor's environment, IL-7 treatment increased T cells in
the blood and immune organs, including the thymus, spleen and lymph nodes,
the investigators found. The therapy also reduced T regulatory cells,
which are known to suppress the immune system in the microenvironment
of brain tumors.

"We are encouraged by the results we are seeing in the mice," said
senior author Dinesh Thotala, PhD, an associate professor of radiation oncology. "We also see evidence that IL-7 could be considered as a
replacement for temozolomide, especially among the nearly 70% of patients
who have a type of tumor that does not respond well to this chemotherapy."
The researchers explained that current immunotherapies called immune
checkpoint inhibitors work by taking the brakes off immune cells that
are already present.

Since so many glioblastoma patients have depleted T cell numbers, it
is perhaps not surprising that immune checkpoint inhibitors have not
proven effective.

"If we are able to increase the number of T cells by giving IL-7, we
would like to find out if adding immune checkpoint inhibitors would
then increase T cell activity against the cancer cells," said Chheda,
who treats patients at Siteman Cancer Center.

Campian, who is now with the Mayo Clinic, said the researchers have
plans to launch a follow-up study in glioblastoma patients at Washington University and the Mayo Clinic to determine whether combining immune
checkpoint inhibitors with long-acting IL-7 boosts survival.

This work was supported by NeoImmuneTech Inc.; the Division of Oncology
Startup Funds, the Department of Radiation Oncology Startup Funds;
the National Institute of Neurological Disorders and Stroke of the
National Institutes of Health (NIH), grant number R01 NS117149; the
Alvin J. Siteman Cancer Research Fund; and the Alvin J. Siteman Cancer
Center Siteman Investment Program through funding from The Foundation
for Barnes-Jewish Hospital and the Barnard Trust.

Campian and Chheda report grants and other support from NeoImmuneTech.

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========================================================================== Journal Reference:
1. Jian L. Campian, Subhajit Ghosh, Vaishali Kapoor, Ran Yan, Sukrutha
Thotala, Arijita Jash, Tong Hu, Anita Mahadevan, Kasem Rifai,
Logan Page, Byung Ha Lee, Sara Ferrando-Martinez, Alexandra
A. Wolfarth, Se Hwan Yang, Dennis Hallahan, Milan G. Chheda,
Dinesh Thotala. Long-acting recombinant human interleukin-7, NT-I7,
increases cytotoxic CD8 T cells and enhances survival in mouse
glioma models. Clinical Cancer Research, 2022; clincanres.0947.2021
DOI: 10.1158/1078-0432.CCR-21-0947 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/01/220118104143.htm

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