Researchers develop a new class of CAR-T cells that target previously untargetable cancer drivers

Date:
November 3, 2021
Source:
Children's Hospital of Philadelphia
Summary:
In a breakthrough for the treatment of aggressive solid cancers,
researchers have developed a novel cancer therapy that targets
proteins inside cancer cells that are essential for tumor growth and
survival but have been historically impossible to reach. Using the
power of large data sets and advanced computational approaches, the
researchers were able to identify peptides that are presented on the
surface of tumor cells and can be targeted with 'peptide-centric'
chimeric antigen receptors (PC- CARs), a new class of engineered
T cells, stimulating an immune response that eradicates tumors.



FULL STORY ==========================================================================
In a breakthrough for the treatment of aggressive solid cancers,
researchers at Children's Hospital of Philadelphia (CHOP) have developed
a novel cancer therapy that targets proteins inside cancer cells that
are essential for tumor growth and survival but have been historically impossible to reach. Using the power of large data sets and advanced computational approaches, the researchers were able to identify peptides
that are presented on the surface of tumor cells and can be targeted with "peptide-centric" chimeric antigen receptors (PC- CARs), a new class of engineered T cells, stimulating an immune response that eradicates tumors.


==========================================================================
The discovery, which was described today in Nature, opens the door
to treating a broader array of cancers with immunotherapy as well as
applying each therapy across a greater proportion of the population.

"This research is extremely exciting because it raises the possibility
of targeting very specific tumor molecules, expanding both the cancers
that can be treated with immunotherapy and the patient population who
can benefit," said Mark Yarmarkovich, PhD, an investigator in the Maris Laboratory at Children's Hospital of Philadelphia and first author of
the paper. "By using a multi-omics approach, we were able to identify
peptides specific to neuroblastoma tumors, but this method could be
used in any cancer, allowing for a more personalized approach to cancer treatment." The development of CAR T cell-based cancer immunotherapy
marked a breakthrough in the treatment of leukemia, but the approach
has not yet made significant strides against solid tumors due, at least
in part, to a lack of tumor-specific targets. In these cancers, most of
the proteins responsible for tumor growth and survival are in the nuclei
of tumor cells, not on the cell surface, where they would generally be accessible to CAR T cells. Instead, fragments of these proteins may be presented on the tumor cell surface through the presentation of peptides
on the major histocompatibility complex (MHC), which evolved to present
viral and bacterial peptides to the immune system. Cancer cells can also present intracellular proteins on MHC, and if these are mutant peptides,
they may be recognized as foreign. However, all pediatric cancers and
many adult malignancies have few mutations and are rather driven by
other factors like dysregulated developmental pathways.

Neuroblastoma is an explosively aggressive pediatric cancer that is
driven by modifications of gene expression that promote uncontrolled
tumor growth.

Historically, neuroblastoma has been treated with chemotherapy,
surgery, and radiation therapy, but patients often relapse with forms
of the disease that are chemotherapy resistant. Additionally, the low mutational burden of the cancer, combined with its low MHC expression,
have made it difficult to target with immunotherapies.

Despite these obstacles, the researchers hypothesized that some of the
peptides presented on the surface of neuroblastoma tumor cells come from proteins that are essential for tumor growth and survival and could
be targeted with synthetic CARs. These PC-CARs would allow for direct
targeting and killing of tumor cells. The challenge was differentiating tumor-specific peptides from other, similar looking peptides or
peptides that exist in normal tissues to avoid cross-reactivity and
lethal toxicity.

To do so, the researchers stripped the MHC molecules off neuroblastoma
cells and determined which peptides were present and at what
abundance. They used a large genomic dataset that the Maris lab has
generated to determine which peptides were unique to neuroblastoma and not expressed by normal tissues. They prioritized peptides that were derived
from genes essential to the tumor and had characteristics required to
engage the immune system. To weed out any potential antigens that might
have cross reactivity with normal tissue, the researchers filtered the remaining tumor peptides against a database of MHC peptides on normal
tissues, removing any peptide with a parent gene represented in normal
tissue.

Using this multi-omics approach, the researchers pinpointed an
unmutated neuroblastoma peptide that is derived from PHOX2B, a
neuroblastoma dependency gene and transcriptional regulator that was
previously identified and characterized at CHOP. The next major hurdle
was developing a PC-CAR that specifically recognized just the peptide,
which makes up 2-3% of the peptide- MHC complex. In collaboration with antibody-discovery company Myrio Therapeutics, the researchers developed
a PC-CAR targeting this peptide and showed that these PC-CARs recognized
the tumor-specific peptide on different HLA types, meaning the treatment
could be applied to patients of diverse genetic lineages.

Taking the research a step further, the team tested the PC-CARs in mice
and found that the treatment led to complete and targeted elimination
of neuroblastoma tumors.

"We are excited about this work because it allows us to now go after
essential cancer drivers that have been considered 'undruggable'
in the past. We think that PC-CARS have the potential to vastly
expand the pool of immunotherapies and significantly widen the
population of eligible patients," said senior author John M. Maris,
MD, pediatric oncologist and Giulio D'Angio Chair in Neuroblastoma
Research at CHOP. "Thanks to the Acceleration grant we received through
the Cell and Gene Therapy Collaborative at CHOP, we will bring our
PHOX2B PC-CAR to a clinical trial at CHOP in late 2022 or early 2023." ========================================================================== Story Source: Materials provided by
Children's_Hospital_of_Philadelphia. Note: Content may be edited for
style and length.


========================================================================== Journal Reference:
1. Mark Yarmarkovich, Quinlen F. Marshall, John M. Warrington, Rasika
Premaratne, Alvin Farrel, David Groff, Wei Li, Moreno di Marco,
Erin Runbeck, Hau Truong, Jugmohit S. Toor, Sarvind Tripathi, Son
Nguyen, Helena Shen, Tiffany Noel, Nicole L. Church, Amber Weiner,
Nathan Kendsersky, Dan Martinez, Rebecca Weisberg, Molly Christie,
Laurence Eisenlohr, Kristopher R. Bosse, Dimiter S. Dimitrov,
Stefan Stevanovic, Nikolaos G. Sgourakis, Ben R. Kiefel, John
M. Maris. Cross-HLA targeting of intracellular oncoproteins with
peptide-centric CARs. Nature, 2021; DOI: 10.1038/s41586-021-04061-6 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/11/211103135824.htm

--- up 8 weeks, 6 days, 8 hours, 25 minutes
* Origin: -=> Castle Rock BBS <=- Now Husky HPT Powered! (1:317/3)