Novel therapeutic strategy shows promise against pancreatic cancer


Date:
March 23, 2022
Source:
Albert Einstein College of Medicine
Summary:
Pancreatic cancer is notoriously difficult to cure or even
treat. Now, a new strategy has succeeded in making pancreatic
tumors visible to the immune systems of mice and vulnerable to
immune attack, reducing cancer metastases by 87%.



FULL STORY ========================================================================== Pancreatic cancer is notoriously difficult to cure or even treat. Now, a
new strategy devised by scientists at Albert Einstein College of Medicine
has succeeded in making pancreatic tumors visible to the immune systems
of mice and vulnerable to immune attack, reducing cancer metastases by
87%. The paper describing the findings published online today in Science Translational Medicine.


========================================================================== "Today's checkpoint inhibitor drugs work well against some types
of cancer but only rarely help people with pancreatic cancer," said
Claudia Gravekamp, Ph.D., corresponding author of the paper and associate professor of microbiology & immunology at Einstein and a member of the
National Cancer Institute-designated Albert Einstein Cancer Center. "The problem is that pancreatic tumors aren't sufficiently 'foreign' to attract
the immune system's attention and can usually suppress whatever immune responses do occur. Essentially, our new therapy makes immunologically
'cold' tumors hot enough for the immune system to attack and destroy
them." Leveraging the Tetanus Vaccine Dr. Gravekamp's treatment strategy capitalizes on the fact that virtually all people are vaccinated in
childhood against tetanus, a serious disease caused by a toxic protein
that Clostridium bacteria secrete. Thanks to their tetanus- specific
memory T cells, which circulate in the bloodstream for life, vaccinated
people will mount a strong immune response if they're later exposed to the highly foreign tetanus toxin. Dr. Gravekamp and her colleagues effectively aroused a potent and specific immune response against pancreatic cancer
cells by infecting them with bacteria that deliver tetanus toxin into
the cells.

Using the same tetanus vaccine given to people, the investigators
vaccinated mouse models of pancreatic cancer (i.e., mice bearing human pancreatic tumors).

They then fused the gene that codes for tetanus toxin into
non-disease-causing Listeria monocytogenes bacteria, which are highly
adept at infecting cells and spreading through tissues. Finally, to
infect and "tetanize" the tumors, they injected the bacteria with their tetanus-gene cargoes into the previously vaccinated, tumor-bearing mice.

Exploiting Cancer's Immune Suppression "The Listeria bacteria are
quite weak and are readily killed off by the immune systems of people
and animals -- everywhere, that is, except in tumor areas," said
Dr. Gravekamp. "Our treatment strategy actually takes advantage of the
fact that pancreatic tumors are so good at suppressing the immune system
to protect themselves. This means that only those Listeria bacteria in the tumor region survive long enough to infect pancreatic tumor cells and that healthy cells don't become infected." Once the Listeria bacteria infected
the tumor cells, their tetanus-toxin genes expressed the tetanus-toxin
protein inside the tumor cells -- triggering a strong immune response. The tetanus toxin activated pre-existing tetanus- specific memory T cells,
causing CD4 T cells to attack and kill the infected tumor cells. The
T cell responses were enhanced by adding low doses of gemcitabine (a chemotherapy drug that reduces immune suppression). The treatment shrank
the size of the pancreatic tumors in the mice by an average of 80% and
also significantly reduced the number of metastases by 87%, while the
treated animals lived 40% longer than untreated (control) animals.

"The findings indicate that this treatment approach could be a useful immunotherapy for pancreatic cancer as well as other types of cancer, such
as ovarian cancer, that remain difficult to treat," said Dr. Gravekamp.

Dr. Gravekamp is an associate professor of microbiology & immunology
at Einstein. Einstein has licensed the underlying technology to Loki Therapeutics., which plans to commercialize the technology further to
benefit patients. Dr. Gravekamp is the co-founder of Loki Therapeutics
and its principal scientist.


========================================================================== Story Source: Materials provided by
Albert_Einstein_College_of_Medicine. Note: Content may be edited for
style and length.


========================================================================== Journal Reference:
1. Benson Chellakkan Selvanesan, Dinesh Chandra, Wilber Quispe-Tintaya,
Arthee Jahangir, Ankur Patel, Kiran Meena, Rodrigo Alberto
Alves Da Silva, Madeline Friedman, Lisa Gabor, Olivia Khouri,
Steven K. Libutti, Ziqiang Yuan, Jenny Li, Sarah Siddiqui, Amanda
Beck, Lydia Tesfa, Wade Koba, Jennifer Chuy, John C. McAuliffe,
Rojin Jafari, David Entenberg, Yarong Wang, John Condeelis, Vera
DesMarais, Vinod Balachandran, Xusheng Zhang, Ken Lin, Claudia
Gravekamp. Listeria delivers tetanus toxoid protein to pancreatic
tumors and induces cancer cell death in mice.

Science Translational Medicine, 2022; 14 (637) DOI: 10.1126/
scitranslmed.abc1600 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/03/220323151658.htm

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