Identification of immunologically protective neo-epitopes for the treatment of cancers
Inventors
Srivastava, Pramod K. • Baker, Brian M.
Assignees
University of Connecticut • University of Notre Dame
Publication Number
US-12311017-B2
Publication Date
2025-05-27
Expiration Date
2035-09-03
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Abstract
Described herein are methods of identifying immunologically protective neo-epitopes from the cancer tissue DNA of cancer patients using biophysical principles as well as bioinformatics techniques. The identification of immunologically protective neo-epitopes provides pharmaceutical compositions with a limited number of tumor-specific peptides suitable for personalized genomics-driven immunotherapy of human cancer. Specifically disclosed herein is a method of using the conformational stability of an epitope in an MHC protein-binding groove to predict immunogenicity of peptides in a putative neo-peptide set from a tumor from a cancer patient. Pharmaceutical compositions and methods of administration are also included.
Core Innovation
The invention provides methods to identify immunologically protective neo-epitopes from cancer tissue DNA of cancer patients by employing biophysical principles and bioinformatics techniques. The central method involves analyzing the conformational stability of candidate neo-epitopes—specifically, the stability of each peptide when bound to a major histocompatibility complex (MHC) protein. Mutant peptides that demonstrate higher conformational stability in the MHC binding groove, compared to their wild type counterparts, are identified as more likely to be immunogenic.
A key problem addressed by this invention is the challenge of distinguishing truly tumor-protective neo-epitopes from the large number of putative neo-epitopes identified through genome- and transcriptome-wide sequencing in tumor samples. Current therapies often lack specificity, leading to limited efficacy and toxic side effects, as treatments like chemotherapy are selective but not cancer-specific. By focusing on tumor-specific DNA differences and using a Differential Agretopic Index (DAI) to prioritize candidate epitopes, the invention narrows down the vast pool of potential peptides to a subset with increased probability of eliciting protective immune responses.
The method includes steps such as sequencing cancer and healthy tissue, deriving putative neo-epitope sets based on sequence differences, ranking the peptides using DAI, and then experimentally or computationally determining their conformational stability when associated with MHC I or II proteins. Epitope candidates with higher stability than wild type sequences are selected for pharmaceutical composition formulation. These compositions may comprise one or more protective neo-epitope peptides, polypeptides, or corresponding polynucleotides, intended for use in personalized genomics-driven immunotherapy of human cancer.
Claims Coverage
The patent claims cover one independent inventive feature describing a method of treating cancer patients through the use of immunologically protective neo-epitopes characterized by specific biophysical properties.
Treatment of cancer with neo-epitopes having higher conformational stability than wild type counterparts
A method of treating a cancer patient comprising administering a pharmaceutical composition that includes: - one or more immunologically protective neo-epitope peptides, - one or more polypeptides containing immunologically protective neo-epitopes, or - one or more polynucleotides encoding the immunologically protective neo-epitopes. The inventive features are: - Each immunologically protective neo-epitope is defined by having higher conformational stability when bound to a major histocompatibility complex class I (MHC I) or class II (MHC II) protein, as determined by molecular modeling or experiment, compared to the corresponding wild type epitope. - Each immunologically protective neo-epitope has a measured IC50 for H-2Kd or human leukocyte antigen (HLA) of greater than 100 nM. - Each neo-epitope is tumor-specific and excludes epitopes derived from known cancer-causing pathways. - The composition may consist of 1 to 100 such peptides or polynucleotides. - The method can include adjuvants or immune-modulating agents. - Applicability for both solid and liquid cancers, with optional combination with other therapies.
The claims focus on a method of treating cancer using neo-epitopes that are uniquely defined by their increased conformational stability versus wild type, significant specificity for tumor antigens, and measured MHC binding properties, enabling targeted immunotherapies.
Stated Advantages
The method reduces the number of potential neo-epitopes to a realistic subset for immunization, enabling personalized and effective cancer immunotherapy.
By focusing on cancer-specific rather than cancer-selective markers, the approach reduces the toxicity of the resulting vaccines.
The approach allows the creation of vaccines with specificity for the actual cancer in the patient, improving treatment specificity.
The methods make it possible to develop non-toxic therapies by leveraging immune therapy instead of traditional drug therapy.
This approach does not rely on known cancer-causing pathways, permitting the design of bespoke medicines for individual tumors.
Documented Applications
Personalized immunotherapy of human cancers by administration of compositions containing immunologically protective neo-epitopes identified through the described method.
Treatment of both solid tumors (such as breast, prostate, ovaries, lungs, and brain cancers) and liquid cancers (such as leukemias and lymphomas).
Use in combination with additional cancer therapies including radiation therapy, chemotherapy, and surgery.
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