Combination immune therapy and cytokine control therapy for cancer treatment
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Publication Number
US-11000548-B2
Publication Date
2021-05-11
Expiration Date
Abstract
Compositions disclosed herein, and methods of use thereof included those for inhibiting or reducing the incidence of cytokine release syndrome or cytokine storm in a subject undergoing CAR T-cell therapy, methods of treating a cancer or tumor, methods of reducing tumor load, methods of reducing the size or growth rate of a cancer or a tumor, and methods of extending of the survival of a subject suffering from a cancer or tumor, wherein the subjects are administered compositions comprising apoptotic cells or apoptotic cell supernatants. Compositions and methods of use thereof may increase the efficacy of a CAR T-cell cancer therapy. Disclosed herein are also compositions and methods of use thereof for decreasing or inhibiting cytokine production in a subject experiencing cytokine release syndrome or cytokine storm. In certain instances compositions may include additional chemotherapeutic or immunomodulatory agents.
Core Innovation
The invention relates to a population of mononuclear apoptotic cells comprising mononuclear cells in an early-apoptotic state, wherein the population is irradiated after production. The irradiated mononuclear apoptotic cell population comprises a decreased percent of non-quiescent non-apoptotic viable cells, and/or suppressed cellular activation of any living non-apoptotic cells, and/or reduced proliferation of any living non-apoptotic cells, compared with a preparation comprising non-irradiated early apoptotic cell populations.
At least 50% of the cells are in an early apoptotic state, the population comprises less than 5% necrotic cells, and the population remains stable at the early-apoptotic state for about 48-72 hours. The described approach is used in CAR T-cell therapy recipients to inhibit or reduce cytokine release syndrome or cytokine storm without diminishing CAR T-cell anti-tumor efficacy.
In this context, early-apoptotic mononuclear cell populations and/or apoptotic cell supernatants are administered to affect the cytokine response after CAR T-cell therapy. The mechanistic framing is that innate immunity/macrophage-associated cytokines are downregulated, while IL-2/IL-2R and T-cell-associated cytokines are relatively unaffected, and pro-inflammatory cytokines including IL-6, IL-1β, and TNF-α are reduced.
Claims Coverage
The claim coverage centers on one independent claim directed to an irradiated mononuclear apoptotic cell population produced in an early-apoptotic state and defined by post-production irradiation, early-apoptotic and stability limitations, and improved characteristics relating to non-quiescent non-apoptotic viable cells, cellular activation, and proliferation. In total, the claim set presents eight inventive features.
Irradiated early-apoptotic mononuclear cell population
A population of mononuclear apoptotic cells comprising mononuclear cells in an early-apoptotic state, wherein said population of mononuclear apoptotic cells is irradiated after production of said early apoptotic cells, and wherein at least 50% of said cells are in an early apoptotic state.
Improved quality versus non-irradiated early apoptotic cells
The irradiated mononuclear apoptotic cell population comprises a decreased percent of non-quiescent non-apoptotic viable cells and/or a suppressed cellular activation of any living non-apoptotic cells and/or a reduced proliferation of any living non-apoptotic cells, compared with a preparation comprising non-irradiated early apoptotic cell populations.
Low necrosis and early-apoptotic stability window
Less than 5% necrotic cells, wherein the population of mononuclear apoptotic cells remains stable at said early-apoptotic state for about 48-72 hours.
Lower non-quiescent non-apoptotic viable cell fraction
The population comprises a decreased percent of non-quiescent non-apoptotic viable cells of less than 10%.
Absence of viable non-apoptotic cells
The mononuclear apoptotic cell population comprises no viable non-apoptotic cells.
Selected mononuclear cell categories
The mononuclear cell population is selected from leukocytes, lymphocytes, monocytes, dendritic cells, and natural killer cells.
Gamma or UV irradiation modalities
The irradiation comprises gamma irradiation or UV irradiation.
Pharmaceutical composition with excipient
A pharmaceutical composition comprising the population and a pharmaceutically acceptable excipient.
Overall, the claims center on an irradiated mononuclear apoptotic cell population produced in an early-apoptotic state and defined by post-production irradiation, low necrosis, and stability for about 48-72 hours, with dependent claims specifying reductions in non-quiescent viable cells, suppression of activation, reduced proliferation, permitted mononuclear cell types, irradiation modality, and formulation as a pharmaceutical composition.
Stated Advantages
Improves CAR T-cell efficacy.
Inhibits or reduces cytokine release syndrome or cytokine storm while not diminishing CAR T-cell anti-tumor efficacy.
Decreases pro-inflammatory cytokine production, including IL-6, IL-1β, and TNF-α.
Downregulates innate immunity/macrophage-associated cytokines, while IL-2/IL-2R and T-cell-associated cytokines are relatively unaffected.
Decreases the percent of non-quiescent non-apoptotic viable cells.
Suppresses cellular activation of any living non-apoptotic cells.
Reduces proliferation of any living non-apoptotic cells.
Maintains stability at the early-apoptotic state for about 48-72 hours.
Delays leukemia/lymphoma disease progression and increases disease-free survival in SCID mice after Raji challenge, with statistically significant survival improvement.
Reduces CD20+ tumor burden in bone marrow and liver.
Provides synergistic survival benefit when combined with rituximab (RtX) and further reduces tumor cell populations.
Improves survival/weight loss and clinical GVHD scoring outcomes in GVHD/leukemia/lymphoma contexts using pooled multiple-donor irradiated apoptotic cell infusions.
Prevents, reduces, or inhibits cytokine release syndrome/cytokine storm by decreasing pro-inflammatory cytokines while maintaining CAR T-cell efficacy.
Modulates macrophages and dendritic cells and increases anti-inflammatory cytokines.
Suppresses inflammatory signaling pathways including TAM receptor signaling (MerTK), PI3K/AKT, NF-κB, and inflammasome-related activity.
Increases tolerogenic dendritic cells.
Documented Applications
Cancer immunotherapy using early-apoptotic mononuclear cell populations and/or apoptotic cell supernatants to improve CAR T-cell efficacy and inhibit or reduce cytokine release syndrome or cytokine storm by decreasing pro-inflammatory cytokine production.
Use of apoptotic cells or apoptotic cell supernatants administered to CAR T-cell therapy recipients to inhibit or reduce cytokine release syndrome or cytokine storm while not diminishing CAR T-cell anti-tumor efficacy.
Use in combination settings showing synergistic tumor control with CAR T therapy and with anti-CD20 (Rituximab).
In vivo leukemia/lymphoma model testing in SCID mice after Raji challenge, including assessment of disease-free survival and tumor burden reduction in bone marrow and liver.
Combination use with rituximab (RtX) in leukemia/lymphoma contexts, with reported synergistic survival benefit and additional reduction of tumor cell populations.
GVHD/leukemia/lymphoma contexts using pooled multiple-donor irradiated apoptotic cell infusions, reporting improved survival/weight loss and clinical GVHD scoring outcomes.
Use in CAR T-cell therapy contexts for preventing, reducing, or inhibiting cytokine release syndrome/cytokine storm.
Combination therapy contexts including CTLA-4 blocking agents such as ipilimumab.
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