Scientists unlock key to designing personalized cancer therapies

Chimeric antigen receptors (CARs) represent a groundbreaking avenue in therapeutic innovation, particularly for rare and challenging cancers. These receptors offer a targeted approach, capable of delivering therapies directly to tumor cells, presenting a promising advancement in cancer treatment.

Peptide-centric CARs (PC-CARs) introduce a unique dimension to this progress by relying on specific peptide “barcodes.” These barcodes, derived from proteins within the cell generated by potentially cancer-causing oncogenes, are meticulously crafted to seek and target cancer cells. Notably, these barcodes are exhibited by human leukocyte antigens (HLAs), which aid the immune system in distinguishing its own proteins from foreign entities like viruses.

The intricacy arises from HLAs being products of highly “polymorphic” genes, boasting over 25,000 alleles. These alleles, distinct stretches of DNA coding for proteins essential in cellular functions, exhibit considerable variation. This variability poses a challenge in designing PC-CARs that effectively target the specific alleles associated with diverse cancers.

A significant breakthrough has emerged from collaborative efforts at the Children’s Hospital of Philadelphia (CHOP). Researchers from closely collaborating labs have unraveled the three-dimensional protein structure crucial for understanding how PC-CARs can identify the “backbones” of HLA complexes. This structural insight now provides researchers with the knowledge to comprehend how CARs recognize tumor-associated antigens within the diverse landscape of polymorphic HLA alleles. This discovery opens up new avenues for precision medicine strategies, particularly in addressing the intricacies of complex and resistant tumors.

Published online in the journal Science Immunology, these findings mark a pivotal step forward in the quest for more effective and tailored therapies against challenging cancers. The newfound understanding of PC-CARs’ interaction with polymorphic HLA alleles paves the way for enhanced precision and customization in the realm of cancer therapeutics.

The movie begins by showing the 10LH CAR : PHOX2B–HLA-A*24:02 complex. The heavy and light chains of the 10LH CAR are colored in purple and green, respectively. The peptide is shown as blue sticks and the HLA is colored in gray. The structure is rotated by 180° and then zooms into the prominent peptide selectivity filter which bridges elements from all three components of the molecular complex. The key HLA residue (Q72) is shown in orange, the key peptide residue (R6) in blue, and key CAR residues in pink (D232 - heavy chain) and green (W88 - light chain). Hydrogen bonds are shown in black dashed lines and a cation-π interaction is shown as a yellow dashed line. The movie then zooms out to show the HLA framework residues along the a1 helix of the HLA. It zooms into the hydrogen bonds between these framework residues and 10LH CDRs. The movie then zooms out again to show the framework residues along the a2 helix of the HLA. Again, hydrogen bonds are shown when zoomed into specific contacts. The movie ends by showing the whole complex again. Credit: Nikolaos Sgourakis

Matching CARs precisely to target the specific alleles associated with certain cancers is crucial to avoid the risk of inducing toxicity without providing therapeutic benefits, warns senior author Nikolaos G. Sgourakis, Ph.D., Associate Professor in the Center for Computational and Genomic Medicine at CHOP. The three-dimensional complex structures revealed in this study offer valuable insights, enabling the design of CARs capable of targeting multiple HLAs and enhancing therapeutic efficiency.

Traditional CAR therapies were limited to targeting cancer-specific antigens on the surface of tumor cells, often residing within the cells. However, recent research uncovered that these previously inaccessible targets eventually break down into peptides, akin to “barcodes,” which can be targeted by therapy. Nevertheless, due to the substantial variability in HLA alleles, CAR therapies may only benefit a fraction of patients, depending on the expressed peptides.

With over 25,000 potentially mutated alleles of HLAs, individually examining them for potential targets is excessively complex. In this study, researchers utilized biochemical binding assays, molecular dynamics simulations, and structural analyses to identify cross-reactivity among certain classes of HLAs. This means that PC-CAR therapy can recognize different antigens with similar backbones, overcoming the variability in peptide barcodes associated with HLAs.

The collaborative efforts of undergraduate and graduate students from the University of Pennsylvania and CHOP senior scientists in the Sgourakis Lab fueled this groundbreaking work. CHOP’s pioneering work in PC-CAR development is evident, with study co-author John M. Maris, MD, publishing an updated paper in Nature on PC-CAR effectiveness. Clinical trials are underway, recruiting patients based on their HLA genotypes to explore the potential of PC-CARs in treating rare and complex cancers.

John M. Maris emphasizes the importance of finding specific targets for T cells to locate tumors safely and effectively. PC-CAR T cells, with their precision in targeting cancer cells over normal healthy cells, offer a promising avenue in treating challenging cancers. The study provides a blueprint for integrating structural biology knowledge into the evolving field of CAR T cell therapies, offering new options for combating formidable cancers.

Source: Children’s Hospital of Philadelphia

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