New approach for cell therapy shows potential against solid tumors with
KRAS mutations
Next step is a clinical trial as soon as 2022

Date:
July 27, 2021
Source:
University of Pennsylvania School of Medicine
Summary:
A new technology for cellular immunotherapy showed promising
anti-tumor activity in the lab against hard-to-treat cancers driven
by the once- considered "undruggable" KRAS mutation, including lung,
colorectal, and pancreatic.



FULL STORY ==========================================================================
A new technology for cellular immunotherapy developed by Abramson Cancer
Center researchers at Penn Medicine showed promising anti-tumor activity
in the lab against hard-to-treat cancers driven by the once-considered "undruggable" KRAS mutation, including lung, colorectal, and pancreatic.


==========================================================================
The study, published online in Nature Communications,successfully
demonstrated using human cells that a T-cell receptor, or TCR, therapy
could be designed to mobilize an immune system attack on mutated KRASsolid tumors and shrink them.

The preclinical work has laid the groundwork for the first-in-human
clinical trial now in the planning stages for the treatment of advanced pancreatic cancer in patients whose tumors harbor specific KRAS mutations
and express a specific type of human leukocyte antigen, or HLA, the
therapy is built to recognize.

"We've shown that targeting mutant KRAS immunologically is feasible and potentially generalizable for a group of patients with lung, colorectal
and pancreatic tumors," said senior author Beatriz M. Carreno, PhD, an associate professor of Pathology and Laboratory Medicine in the Perelman
School of Medicine at the University of Pennsylvania and a member of
the Center for Cellular Immunotherapies, the Abramson Cancer Center,
and Parker Institute for Cancer Immunotherapy at Penn. "We look forward
to taking this research to the next level and closer to clinical study."
KRAS mutations are among the most prevalent mutations observed in cancers
and have been shown to drive tumor development and growth. Only recently
have targeted therapies been shown to successfully treat a specific
KRAS mutation found most commonly in lung cancer; however, no treatments currently exist for the majority of other KRAS mutations more prevalent
in other tumor types.

Immunological targeting of mutant KRAS represents an alternative treatment approach but has been less studied and understood.

Using a multiomics approach, the Penn team identified specific neoantigens associated with mutations at the G12 site on the KRAS gene. Neoantigens
are protein fragments that form on the cancer cell surface when certain mutations occur in tumor DNA. More than 75 percent of the alterations
in the KRAS protein occur at G12, making it an ideal site to target
with therapies.

Armed with this knowledge, the researchers tested a TCR therapy directed
toward specific KRAS G12 mutations present in conjunction with particular
HLA types highly prevalent among patients. They showed in a mouse
tumor model that it was effective at attacking and eliminating tumor
cells. HLAs are an important part of the immune system because they
encode cell surface molecules that present specific neoantigens to the
T-cell receptors on T cells.

In other words, HLAs are key genetic codes needed for these engineered
T cells to find and attack tumors.

The research further supports the use of neoantigens for targeting tumor
cells, for both cellular therapy and cancer vaccines, which have been
underway at Penn Medicine and elsewhere.

Importantly, the neoantigen and HLA information from this latest study
is being used to develop TCR therapies to treat solid tumors, as well as
new cancer vaccines. Based off these latest findings, the team initiated
a vaccine clinical trial led by Mark O'Hara, MD, an assistant professor
of Hematology- Oncology at Penn and co-author on the study, in pancreatic cancer targeting mutated KRAS.

The first clinical trial for the TCR therapy is projected to launch
as soon as 2022, depending on regulatory approval, at Penn's Abramson
Cancer Center for patients with advanced pancreatic cancer who have
both the KRAS mutation and specific HLA types identified in this
latest study -- which could represent up to 10 percent of patients
with pancreatic cancer. The study opens the door, however, to expand
the patient population as researchers continue to discover more about
the neoantigens derived from regions of the KRAS gene and other mutated oncogenes implicated in driving cancer.

"We provide evidence that this oncogenic protein is a very promising
clinical target of immune-based therapies," said lead author Adham
Bear, MD, PhD, an instructor in the division of Hematology-Oncology
at Penn and member of the Parker Institute for Cancer Immunotherapy at
Penn. "The goal, now that we have identified these neoantigens and T cell receptors, is to translate these findings and apply them to develop new therapies at Penn." The study was supported by the National Institutes
of Health (R01 CA204261, P30 CA016520, CA196539 and CA232568), The
Stand Up to Cancer/Lustgarten Foundation Pancreatic Cancer Collective,
the Penn Institute for Immunology, and the Parker Institute for Cancer Immunotherapy.

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


========================================================================== Journal Reference:
1. Adham S. Bear, Tatiana Blanchard, Joseph Cesare, Michael J. Ford,
Lee P.

Richman, Chong Xu, Miren L. Baroja, Sarah McCuaig, Christina
Costeas, Khatuna Gabunia, John Scholler, Avery D. Posey, Mark
H. O'Hara, Anze Smole, Daniel J. Powell, Benjamin A. Garcia, Robert
H. Vonderheide, Gerald P. Linette, Beatriz M. Carreno. Biochemical
and functional characterization of mutant KRAS epitopes validates
this oncoprotein for immunological targeting. Nature Communications,
2021; 12 (1) DOI: 10.1038/s41467-021-24562-2 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/07/210727131451.htm

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