Methods of preparing an isolated population of dendritic cells and methods of treating cancer using same
Inventors
Cafri, Gal • Robbins, Paul F. • Gartner, Jared J. • Rosenberg, Steven A.
Assignees
US Department of Health and Human Services
Publication Number
US-11976299-B2
Publication Date
2024-05-07
Expiration Date
2037-09-18
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Abstract
Disclosed are methods of preparing an isolated population of dendritic cells, isolated populations of dendritic cells prepared by the methods, and pharmaceutical compositions comprising the isolated population of dendritic cells. Also disclosed are methods of treating or preventing cancer using the isolated population of dendritic cells or pharmaceutical compositions.
Core Innovation
The invention provides methods of preparing an isolated population of dendritic cells, pharmaceutical compositions comprising the isolated dendritic cells, and methods of treating or preventing cancer using these compositions. An embodiment includes identifying mutated amino acid sequences encoded by cancer-specific mutations, inducing dendritic cells from a patient to present these mutations, co-culturing patient T cells with these dendritic cells, selecting mutated sequences for which T cells show antigenic specificity, generating a second dendritic cell population from patient monocytes to present the selected mutations, maturing these dendritic cells, and formulating an isolated population of matured dendritic cells that present the selected mutated sequences.
The problem addressed is the limitations in therapeutic vaccines against established diseases such as cancer. Specifically, vaccines may induce T cell depletion of high avidity clones directed against target antigens, leading to loss of T cells bearing high-affinity T cell receptors with superior cytotoxic capacity, longer persistence in the tumor microenvironment, and decreased susceptibility to immune suppression. This depletion impairs clinical vaccine efficiency. Thus, improved methods for preparing compositions useful in cancer treatment or prevention are needed.
The method distinguishes immunogenic cancer-specific mutated amino acid sequences from silent or non-immunogenic mutations and targets neoantigens derived from somatic mutations, which are believed to avoid disadvantages of central immunological tolerance seen with differentiation antigens and other common antigen types. The invention provides rapid assessment of mutations restricted by all patient MHC molecules, enabling identification of the full repertoire of mutations recognized by T cells. The resulting personalized dendritic cells presenting these mutations may better stimulate immune responses to cancer, reducing off-target toxicity and improving clinical efficacy compared to other antigen targeting approaches.
Claims Coverage
The patent includes one independent claim with several inventive features related to a method of inducing an immune response against mutated amino acid sequences in a patient.
Identification of mutated amino acid sequences encoded by cancer-specific mutations
The method involves identifying one or more mutated amino acid sequences, each encoded by a gene containing a cancer-specific mutation.
Loading dendritic cells with peptides comprising mutated amino acid sequences
Inducing first dendritic cells from the patient to present the mutated sequences by loading them with peptides or pools of peptides, each comprising different mutated amino acid sequences.
Co-culturing patient T cells and selecting mutated sequences with antigenic specificity
Co-culturing patient T cells with first dendritic cells and selecting mutated amino acid sequences for which the T cells show antigenic specificity involving recognition in the context of MHC Class I and II molecules.
Differentiating monocytes into second dendritic cells presenting selected mutations
Isolating monocytes and differentiating them into second dendritic cells which are induced to present the selected mutated amino acid sequences by peptide loading.
Maturing second dendritic cells with specific agents and phenotypic criteria
Maturing the second dendritic cells in the presence of polyinosinic-polycytidylic acid (polyI:C), resiquimod (R848), and interferon gamma, in absence of further stimulating agents, resulting in a population expressing above 70% CD11c and CD86.
Administration of matured dendritic cells to induce immune response
Administering the matured second dendritic cells which present the selected mutated amino acid sequences to the patient to induce an immune response against these sequences.
These inventive features together describe a detailed method of isolating, inducing, selecting, maturing, and administering patient-specific dendritic cells presenting cancer-specific mutated amino acid sequences to effectively induce immune responses against cancer.
Stated Advantages
Rapidly assesses a large number of mutations restricted by all patient MHC molecules simultaneously, identifying a full repertoire of cancer-specific mutations recognized by patient's T cells.
Targets neoantigens derived from somatic mutations, potentially avoiding issues of immune tolerance associated with differentiation, cancer testis, and overexpressed antigens.
Provides personalized dendritic cells presenting unique patient mutations, improving clinical efficacy compared to therapies targeting common antigens.
Selective targeting of immunogenic mutated amino acid sequences reduces off-target toxicity and minimizes destruction of normal cells.
The described dendritic cell maturation protocol (polyI:C, R848, IFN-γ without additional stimuli) efficiently generates mature DCs secreting pro-inflammatory cytokines important for T cell activation.
Documented Applications
Treatment or prevention of cancer in a patient by administering the isolated population of dendritic cells or pharmaceutical compositions comprising them.
Use as a cancer vaccine to elicit T cell immune responses targeting personalized cancer-specific mutated amino acid sequences.
Adoptive cell therapies using the prepared dendritic cells to stimulate T cells for anti-cancer therapy.
Potential use in treatment of various cancers including melanoma, colorectal, ovarian, lung, breast, pancreatic, and others as exemplified in the description.
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