"Our next steps are to move the PHOX2B PC-CAR into a clinical trial in late 2022, develop additional PC-CARs for neuroblastoma, and discover PC-CAR targets in other important childhood cancers," Dr. John Maris of Children's Hospital of Philadelphia (CHOP) told Reuters Health by email.
PHOX2B is a neuroblastoma dependency gene and transcriptional regulator, previously identified and characterized at CHOP.
Although the approach is ready for testing in humans now, Dr. Maris said, "We need to build the clinical grade PC-CAR for about 100 patients, which will take about a year. Cell manufacturing is an expensive and time-consuming process."
As reported in Nature, Dr. Maris and colleagues stripped the MHC molecules off neuroblastoma cells and determined which peptides were unique to neuroblastoma. They prioritized peptides derived from genes essential to the tumor that could engage the immune system.
They pinpointed an unmutated, tumor-specific peptide derived from PHOX2B called QYNPIRTTF. They then developed PC-CARs that targeted QYNPIRTTF and, using computational modeling, showed that these PC-CARs could recognize the peptide on different HLA types, meaning the treatment could be applied to patients with diverse genetic lineages.
The team then tested the PC-CARs in mice and showed complete neuroblastoma tumor regression.
The authors state, "These data suggest that peptide-centric CARs have the potential to vastly expand the pool of immunotherapeutic targets to include non-immunogenic intracellular oncoproteins and widen the population of patients who would benefit from such therapy by breaking conventional HLA restriction."
Dr. Crystal Mackall, Director of the Stanford Center for Cancer Cell Therapy and of the Parker Institute for Cancer Immunotherapy at Stanford, commented on the study in an email to Reuters Health.
"The approach is quite novel and the data presented demonstrate proof-of-concept that non-mutant molecules overexpressed in cancer, but not expressed on the cell membrane, can be targeted with CAR-T cells," she said.
"These novel PC-CARs appear not to be major histocompatibility complex (MHC)-restricted in this traditional sense, but they are also not truly MHC-independent," she noted. "More work is needed to better understand how much the MHC molecule contributes to the response and thus breadth of the population that benefit from a PC-CAR."
"The work provides evidence for specificity, but given previous challenges with toxicities in some trials targeting tumor-associated peptides with engineered T-cell receptors, the potential for toxicity due to cross-reactivity will need to be monitored closely," she said.
"This work is extremely exciting because of its novelty and the potential to expand the catalogue of targets for cancer immunotherapy," she added. "But with novelty comes a lack of full understanding. I look forward to additional work using this platform to better credential it as a safe and effective immunotherapy."
Dr. Paul Sondel, Director of Research in the Division of Pediatric Hematology, Oncology and Bone Marrow Transplant and Co-leader of the UWCCC Working Group in Cancer Immunology and Immunotherapy at the University of Wisconsin in Madison, also commented by email.
"This approach, and the example detailed here, suggests that it may be possible to create a receptor that could be put into T cells from any cancer patient, that will then have the capability of specifically recognizing and destroying their own cancer, without harming normal cells," he said.
"This novel and ingenious strategy, if generalizable to other solid tumors (which seems reasonable), presents a potential pathway to enable creation of cancer-reactive immune cells that may have the ability to specifically recognize and destroy virtually any type of cancer cell that expresses a modest amount of HLA molecules," he noted.
"Important safety, and then efficacy, studies will be needed," he noted. "In vivo efficacy may require combining these novel PC-CAR-T cells with other immunomodulatory therapies that can facilitate the ability of CAR-T cells that kill tumor well in vitro to be able to be effective against solid tumors in vivo."
"These next steps are essential," he added, "but the strength of this new work suggests that some aspect of (it) will likely be influencing future cancer treatment."
SOURCE: https://go.nature.com/3EVZpqX Nature, online November 3, 2021.
By Marilynn Larkin
Posted on
site created by:
© 2024 Medicom Medical Publishers. All rights reserved. Terms and Conditions | Privacy Policy