KRAS peptide vaccine compositions and method of use
Inventors
Pan, Jing • You, Ming • LUBET, Ronald
Assignees
Medical College of Wisconsin • National Institutes of Health NIH
Publication Number
US-11771749-B2
Publication Date
2023-10-03
Expiration Date
2038-02-05
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Abstract
The present disclosure provides compositions and methods of eliciting an anti-tumor immune response and treating cancer comprising at least one peptide of KRAS.
Core Innovation
The invention provides vaccine compositions and methods for the treatment and prevention of cancer by eliciting an anti-tumor immune response using at least one peptide of KRAS. The peptides, typically 15-17 amino acids in length, are specifically selected for their ability to bind MHC class II molecules and provoke a robust immune response. Combinations of MHC class II peptides, optionally with MHC class I peptides of KRAS, are used to stimulate a strong anti-tumor reaction in subjects.
This disclosure addresses the lack of effective therapies targeting mutant KRAS, a protein frequently mutated in various cancers including lung, pancreatic, and colon cancer. Traditional targeted therapies have been limited because KRAS lacks druggable pockets on its surface. Instead, this invention leverages peptide vaccination targeting tumor-associated antigens to induce memory T cells capable of recognizing and destroying KRAS-expressing cancer cells.
The invention demonstrates the immunogenicity and antitumor efficacy of a multipeptide KRAS vaccine in mouse models of KRAS-driven lung tumors, showing its utility in prevention and possible treatment of various cancers with KRAS involvement. The compositions described include KRAS peptides, vectors encoding these peptides, adjuvants, and may be administered prior to or after conventional therapies, or in combination with checkpoint inhibitors and other agents.
Claims Coverage
The patent claims cover several inventive features centered on KRAS peptide-based vaccines, methods of eliciting anti-tumor immune responses, and combinations with adjuvants and other agents.
Vaccine composition comprising at least four peptides of KRAS
A vaccine composition that includes at least four peptides of KRAS, where the peptides are selected from SEQ ID Nos. 1–12, and at least one of the peptides is selected from SEQ ID NO: 7, 8, 9, 10, 11, or 12. The composition may alternatively include one or more vectors encoding four KRAS peptides from the same group, and contains an adjuvant. The composition elicits an anti-tumor immune response in a subject.
Vector comprising nucleic acid sequences encoding the KRAS peptides
A vector containing an isolated nucleic acid sequence encoding the KRAS peptides described above, operatively linked to a heterologous transcriptional regulatory element.
Method of eliciting an anti-tumor immune response using the KRAS vaccine composition
A method for eliciting an anti-tumor immune response in a subject by administering an effective amount of the vaccine composition comprising at least four KRAS peptides or vectors encoding them, as described, in combination with an adjuvant.
Method for reducing tumor cells or tumor size
Using the vaccine composition, the method reduces the number of tumor cells or tumor size in the subject.
Combination therapies including checkpoint inhibitors, NSAIDs, RXR agonists, or avasimibe
Combination of the vaccine composition with at least one checkpoint inhibitor (e.g., PD-L1 antibody, VISTA antibody, TIM3 antibody, CTLA-4 antibody, or PD-1/PD-L1 peptide or inhibitor), NSAIDs, RXR agonists (e.g., bexarotene, UAB30, low dose retinoic acid), or avasimibe to enhance anti-tumor effect.
Method for reducing or slowing progression or development of cancer in at-risk patients
A method to reduce or slow the progression or development of cancer in patients at risk of developing a KRAS-associated cancer, comprising determining risk (such as detecting a KRAS mutation) and treating with the described vaccine composition, optionally in combination with avasimibe, checkpoint inhibitors, or RXR agonists.
Collectively, the inventive features define vaccine compositions containing selected KRAS peptides or their encoding nucleic acids, use of specific adjuvants, various methods for inducing anti-tumor immune responses, personalized cancer prevention and treatment strategies, and combination therapy regimens with immunomodulators or other agents.
Stated Advantages
The KRAS peptide vaccine demonstrates striking efficacy, reducing tumor number and burden by over 80% in mouse models compared to adjuvant alone.
The vaccine elicits robust antigen-specific, Th1 and Th17 immune responses associated with anti-tumor activity.
The approach has potential utility in both the prevention and treatment of KRAS-driven cancers, either alone or in combination with other modalities.
The KRAS peptides show high sequence homology between mouse and human, supporting clinical translatability of the vaccine.
The compositions enable effective immune responses against mutant and wild-type regions of KRAS, broadening potential patient applicability.
Combination of the KRAS peptide vaccine with checkpoint inhibitors, RXR agonists, NSAIDs, or avasimibe can achieve additive or synergistic anti-tumor effects.
Documented Applications
Treatment and prevention of KRAS-associated cancers including lung cancer, pancreatic cancer, and colon cancer.
Primary and secondary prevention of KRAS-induced lung cancer in mouse models, including carcinogen-induced models.
Reduction of tumor numbers and tumor load in pancreatic and colon cancer models.
Use in combination with checkpoint inhibitors (anti-PD-L1, anti-VISTA, anti-TIM3, anti-CTLA-4 antibodies, PD-1/PD-L1 peptides or inhibitors) for enhanced anti-tumor efficacy.
Use in combination with RXR agonists (bexarotene, UAB30, low dose retinoic acid), NSAIDs, or avasimibe for improved or synergistic anti-tumor effects.
Prevention or slowing of cancer progression in patients at risk of KRAS-associated cancers by testing for KRAS mutations and vaccinating accordingly.
Planned phase I study administering the KRAS/PD-1/PD-L1 peptide vaccine in patients with resectable pancreatic, lung, or colon cancer post-surgery with monitoring for immune response and recurrence.
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