It is mind-boggling that a company that has an exclusive licence...

It is mind-boggling that a company that has an exclusive licence to develop and commercialise Penn's CDH17 CAR T cell therapy, combined with a non-exclusive “know-how license” to use Penn’s third-generation lentiviral vector plasmid system, is sitting at a MC A$53 million.

We have all heard of the first gene therapy approved by the FDA back in 2017, Kymriah (tisagenlecleucel), which happens to come with some heavy side-effects (CRS, other neurological events and serious infections).
(for anyone wondering, bold means there's a link to the source of the statement)

Kymriah earned $587 million last year, a 24% gain.

The drug was developed at Penn by Carl H. June, MD in collaboration with Novartis Pharmaceuticals. Penn originally teamed with Novartis in 2012 after researchers from Penn’s Abramson Cancer Center published their findings on the use of CAR T cells to treat patients with chronic lymphocytic leukemia.

Carl June, A pioneer in CAR-T therapies has been named one of Time Magazine’s 100 most influential people in the world for 2018.

The Neuroendocrine Tumor Research Foundation (NETRF) is the leading private funder of research into causes and treatments of neuroendocrine tumors (NETs) to improve and extend the lives of those living with NETs. The Foundation’s first grant was to a pioneer of this therapy Carl June, M.D., and his colleagues Xianxin Hua, M.D., Ph.D., and David Metz, M.D., at the University of Pennsylvania. These colleagues continue to collaborate on NET research, with Dr. Hua leading an ongoing study.

“These recent advances raise an exciting possibility that NETs can be specifically targeted via specific CAR T cells to effectively eradicate NET cells,” said Xianxin Hua, M.D., Ph.D.

Most of the early CAR T-cell research focused on blood cancers, especially lymphoiblast leukemia, because these leukemia cells express a highly lineage-specific cell surface antigen that can be targeted by CAR T cells to eradicate the antigen-bearing cells including the leukemia cells. While NET cancer cells do not express a NET cell-specific cell surface antigen, NET cells tend to express abnormally high levels of somatostatin receptors (SSTRs) on their surface. Researchers hope that SSTR can serve as the antigen that attracts the killer CAR T cells.
The first step in using this technology in NETs is to develop receptors to recognize SSTR as an antigen on surface of the neuroendocrine tumor cell. Dr. Hua and colleagues have developed a CAR system that can attach to SSTR-expressing tumor cells and kill the cancer cell. They have successfully tested the receptors in cultures, laboratory models, and are preparing next to test them in freshly isolated human tumor cells.“These studies will likely lead to the development of an entirely new and more effective therapy for NET patients who have failed previous treatments and save their life,” said Dr. Hua.


PROJECT TITLE:
Developing novel treatments for NETs using CAR T-Cell Technology
General Description
Adoptive T-cell therapy involves engineering chimeric antigen receptors (CARs), which specifically target tumor associated antigens. This approach has had dramatic results in patients with other cancers. Success in this project could pave the way for trials of this breakthrough technology for neuroendocrine tumors. The team will first develop CAR T-cells designed to eradicate neuroendocrine tumors via targeting somatostatin receptors on the surface of the neuroendocrine tumor cells. Second, the best CAR T-cells will be tested for their capability to specifically kill the cancer cells in cultured cells.These studies will aid the development of an entirely new and effective therapy for neuroendocrine tumor patients who have failed previous treatments. This project relies on the expertise of Carl June, MD, renowned for his work in immunotherapy. In particular, Dr. June’s team spent many years developing CAR T-cell “serial killer”, which have been successful in treating patients with forms of leukemia and other cancers. This project brings together the multi-disciplinary team of Xianxin Hua, Carl June, and David Metz to develop CAR T-cells to target receptors found on neuroendocrine tumor cells and then kill those cells.


"[...] So it's been about 20 years just making the platform of how to make the T cells be reprogrammed, so that they could then be this CAR T cell. And now it's actually not so difficult because it is only one part that needs to be swapped out. It's just like changing the program a little bit and then now they could be NET specific rather than leukaemic specific T cells. [...]"


With funding from NETRF, CAR T-cell therapy is being tested on neuroendocrine tumors (NETs). In 2014, NETRF funded Dr. June and colleagues XianXin Hua, MD, PhD, and David Metz, MD, at the University of Pennsylvania to investigate this novel approach. Since that time, NETRF has extended funding for the group with Dr. Hua taking the lead in laboratory experiments.

“NETRF recognized the value of this emerging technology and approached Dr. June to test it in NETs,” said Effie Tzameli, PhD, NETRF Director of Research. “The surface of a NET cell is different than normal cells, which may make it easier for a CAR to recognize and attack.”

Dr. Hua is testing the effectiveness of a new CAR (SSTR2) capable of recognizing and attacking NET cells. In laboratory models, Dr. Hua and colleagues are studying whether the experimental NET CAR (SSTR2) is as safe and effective as the leukemia CAR (CD19) in killing cancer cells (and not healthy cells). These studies will continue until early 2018. If SSTR2 proves safe and effective in laboratory testing, it could be testing in humans in the early 2020s.


These studies made headlines back in March 2022, when the results were published in nature cancer, Potent suppression of neuroendocrine tumors and gastrointestinal cancers by CDH17CAR T cells without toxicity to normal tissues.


Penn Medicine News mentioned in a News Release:

“Our work demonstrates that CDH17CAR T cells can eliminate solid tumors like NETs and GICs, but do not damage healthy, normal tissues that also express CDH17, because CDH17 is sequestered and hidden between the normal cells,” said senior author Xianxin Hua, MD, PhD, a professor in the Department of Cancer Biology in the Abramson Family Cancer Research Institute at Penn. “This opens avenues to explore a new class of tumor antigens that are also expressed in normal cells but protected by the CAR T cell attack and is hopefully another important step in developing safer immunotherapies for solid tumors.”

GICs and NETs are often fatal once they have spread. There are about five million new cases of GICs annually worldwide, underscoring the need for scientific and clinical advancements.

“Now that we have identified CDH17 as a promising new class target, we can take a multipronged approach to target CDH17 and launch a phase 1 study to treat drug-resistant NETs and GICs,” said first author Zijie Feng, a research scientist in the department of Cancer Biology at Penn. “The CDH17 CAR T cells may be particularly suitable for patients with solid tumors, and these findings motivate additional investigation of CAR Ts that can be developed against previously written-off tumor-associated antigens.”

Other Penn researchers on the study include Carl H. June, MD, the Richard W. Vague Professor in Immunotherapy in the Department of Pathology and Laboratory Medicine; Bryson Katona, MD, PhD, director of the Gastrointestinal Cancer Genetics Program; Terence P. Gade, MD, PhD, co-director of the Penn Image-Guided Interventions Laboratory; and David C. Metz, MBBCh, a professor CE of Medicine in the Divison of Gastroenterology and Hepatology.

In 2021, the University of Pennsylvania and Chimeric Therapeutics, Limited entered into an exclusive licensing agreement for the first CDH17 CAR T cell therapy to be explored for clinical research.

This study was funded by a Care for Carcinoid Foundation Research Grant and a Neuroendocrine Tumor Research Foundation (NETRF) Accelerator Grant.

Editor’s Note: Penn has licensed certain Penn-owned intellectual property to Chimeric Therapeutics, Limited. (“Chimeric”), and the Perelman School of Medicine at the University of Pennsylvania receives sponsored research funding from Chimeric in support of Dr. Hua’s laboratory. Penn and Drs. Hua and Feng are entitled to receive future financial benefits from development and commercialization of technologies licensed and optioned to Chimeric.

https://www.pennmedicine.org/news/news-releases/2022/march/penn-developed-car-t-cells-suppress-gi-solid-tumor-cells-without-toxicity-to-healthy-tissue


A$53 million...