New target for CAR T cells in solid tumors
Chimeric antigen receptor T cells that target OR2H1 inhibit lung and
ovarian tumor growth in mice

Date:
May 4, 2022
Source:
H. Lee Moffitt Cancer Center & Research Institute
Summary:
Researchers share the identification of a new potential target
for CAR T cells called OR2H1 that they have demonstrated inhibits
growth in lung and ovarian tumors.



FULL STORY ========================================================================== Chimeric antigen receptor T-cell therapy, or CAR T, has made a big
impact on the treatment of certain blood cancers, allowing patients
with relapsed/ refractory disease to live longer, healthier lives. But
in clinical study, the cellular therapy has not been as successful for
patients with solid tumors, due in part to the lack of tumor targets
not expressed in vital tissues. In a new study published in Molecular
Cancer Therapeutics, a journal of the American Association for Cancer
Research, Moffitt Cancer Center researchers share the identification
of a new potential target for CAR T cells called OR2H1 that they have demonstrated inhibits growth in lung and ovarian tumors.


==========================================================================
The key to CAR T-cell therapy is the genetic modification made to the
patient's T cells. Their cells are collected through a process called apheresis, and then shipped to a laboratory where the cells are modified
to contain a gene for the T cell receptor that recognizes a specific
marker on cancer cells. Those modified T cells, now CAR T cells, are
stimulated to grow and multiply before being sent back to the hospital
to be infused back into the patients. The receptor on the CAR T cells
acts as a GPS, seeking out their specific marker on the surface of the
cancer cells. Currently there are CAR T therapies approved to treat
patients with lymphoma, leukemia and multiple myeloma, but there are no approved CAR T therapies for solid tumors.

Moffitt researchers are working to identify tumor markers that can make
CAR T an effective therapy for patient with solid tumors. The goal is to
find a marker that is expressed on tumor cells but not on normal cells,
to reduce the potential for unwanted toxicities. The team, led by Dr. Jose Conejo-Garcia, focused the search on a family of proteins called olfactory receptors that are expressed in the nose and contribute to the perception
of smell. During lab experiments, they discovered that the protein OR2H1
is expressed in a variety of solid tumors, ranging from 4% of colon cancer samples to 69% of cancers of the gall bladder. Importantly, of all normal tissues examined, OR2H1 was found only in the testis, suggesting that
therapies that target OR2H1 would have minimal effects on normal cells.

The researchers then created CAR T cells that were specific to the OR2H1 protein. The OR2H1 CAR T cells were able to kill lung and ovarian cancer
cells that expressed OR2H1 but had no effect on healthy cells. The OR2H1
CAR T cells also had anti-tumor effects in vivo in immunodeficient mice challenged with human tumors. Tumor inhibition was observed in lung
and ovarian cancer mice models with varying levels of OR2H1, including
ovarian cancer cells that were resistant to chemotherapy.

These combined data suggest that OR2H1 may be an effective target for CAR
T therapies in solid tumors. The researchers hope these initial studies
will lead to the development of OR2H1 CAR T cells for a wide variety of patients with solid tumors.

"Our work demonstrates the applicability of this therapy to a wide
variety of patients, given the expression of OR2H1 in a subset of solid
tumors across multiple histologies, including high-grade serous ovarian cancers, lung carcinoma, cholangiocarcinoma, prostate cancer and ovarian cancers of multiple other histologies. Targeting a molecule that is not expressed in vital tissues would allow us to further engineer T cells to overcome immunosuppression at tumor beds, if needed," said Conejo-Garcia,
chair of Moffitt's Department of Immunology.

This work was supported by the National Cancer Institute (P30CA076292, R01CA157664, R01CA124515, R01CA178687, R01CA211913, U01CA232758,
T32CA009140, K99CA266947), the Moffitt Foundation, Moffitt's Junior
Scientist Research Partnership Award and the American Cancer Society Postdoctoral Fellowship.


========================================================================== Story Source: Materials provided by H._Lee_Moffitt_Cancer_Center_&_Research_Institute. Note: Content may be
edited for style and length.


========================================================================== Journal Reference:
1. Alexandra L. Martin, Carmen M. Anadon, Subir Biswas, Jessica
A. Mine,
Katelyn F. Handley, Kyle K. Payne, Gunjan Mandal, Ricardo
A. Chaurio, John J. Powers, Kimberly B. Sprenger, Kristen
E. Rigolizzo, Patrick Innamarato, Carly M. Harro, Sumit Mehta,
Bradford A. Perez, Robert M.

Wenham, Jose R. Conejo-Garcia. Olfactory Receptor OR2H1 is
an effective target for CAR T cells in human epithelial
tumors. Molecular Cancer Therapeutics, 2022; DOI:
10.1158/1535-7163.MCT-21-0872 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/05/220504110424.htm

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