Methods for improving adoptive cell therapy
Inventors
Riddell, Stanley R. • Srivastava, Shivani
Assignees
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Publication Number
US-12350312-B2
Publication Date
2025-07-08
Expiration Date
Abstract
The present disclosure provides reagents and methods for treating disease using modified immune cells (e.g., T cell comprising CAR or TCR) in combination with an agent associated with induction of immunogenic cell death (ICD) and optionally further in combination with an agent that specifically binds to and/or inhibits an immune suppression component and/or an agonist of an immune stimulatory molecule.
Core Innovation
The invention relates to treating solid tumors in a subject using adoptive cell therapy with a T cell comprising a heterologous polynucleotide encoding a chimeric antigen receptor (CAR) that specifically binds to a ROR1 cell-surface antigen expressed by tumor cells. The CAR T cell can comprise CD4+ T cells, CD8+ T cells, stem cell memory T cells, or any combination of these. In the documented framework, this CAR-based approach is combined with agents that induce immunogenic cell death and with checkpoint inhibition targeting PD-1 or PD-L1.
The method includes administering an effective amount of oxaliplatin, or an active metabolite or derivative thereof, and an effective amount of cyclophosphamide, with their administration occurring prior to the administration of the CAR T cell and a PD-1 or PD-L1 inhibitor. Separately, the method also administers an effective amount of an antibody or antigen-binding fragment that specifically binds to and is an inhibitor of PD-1 or PD-L1. The checkpoint inhibition can be provided as an inhibitor of PD-1 or PD-L1 as recited in the claims.
In the described preclinical context, CAR T cells initially show limited tumor trafficking and/or efficacy and can upregulate PD-1, leading to examination of PD-1 blockade. PD-1 blockade alone is stated not to improve anti-tumor efficacy, while combining immunogenic cell death-inducing chemotherapy with anti-PD-L1 alongside anti-ROR1 CAR T therapy is described as synergistically improving tumor control. The documented results further describe increased intratumoral CD3/CD8 infiltration and associations with changes in the immunosuppressive tumor microenvironment, including effects on Tregs and MDSCs.
Claims Coverage
The document includes five independent method claims and an additional independent method claim directed to a specific tumor context. Across these independent claims, the inventive coverage centers on CAR T targeting of a ROR1 cell-surface antigen combined with PD-1/PD-L1 inhibition and prior administration of oxaliplatin and cyclophosphamide, with optional refinements specifying the timing/sequence, CAR architecture elements, and treatment of ROR1+ solid tumor subsets.
ROR1-targeting CAR T with PD-1/PD-L1 inhibition after oxaliplatin and cyclophosphamide
Administering an effective amount of a T cell comprising a heterologous polynucleotide that encodes a CAR that specifically binds to a ROR1 cell-surface antigen expressed by tumor cells, together with an effective amount of an antibody or antigen-binding fragment that specifically binds to and is an inhibitor of PD-1 or PD-L1, where prior to administering the T cell and antibody the subject has been administered oxaliplatin or an active metabolite or derivative thereof and cyclophosphamide.
PD-1/PD-L1 inhibition after prior CAR T, oxaliplatin, and cyclophosphamide
Administering an effective amount of an antibody or antigen-binding fragment that specifically binds to and is an inhibitor of PD-1 or PD-L1, where prior to administering the antibody or fragment the subject has been administered a T cell comprising a CAR that specifically binds to a ROR1 cell-surface antigen, oxaliplatin or an active metabolite or derivative thereof, and cyclophosphamide.
CAR T with prior PD-1/PD-L1 inhibition, oxaliplatin, and cyclophosphamide
Administering an effective amount of a T cell comprising a CAR that specifically binds to a ROR1 cell-surface antigen expressed by tumor cells, where the subject, prior to administering the T cell, has been administered an antibody or antigen-binding fragment that specifically binds to and is an inhibitor of PD-1 or PD-L1, oxaliplatin or an active metabolite or derivative thereof, and cyclophosphamide.
Oxaliplatin plus CAR T plus PD-1/PD-L1 inhibitor with prior cyclophosphamide
Administering to the subject an effective amount of oxaliplatin or an active metabolite or derivative thereof, an effective amount of a T cell comprising a CAR that specifically binds to a ROR1 cell-surface antigen expressed by tumor cells, and an effective amount of an antibody or antigen-binding fragment that specifically binds to and/or is an inhibitor of PD-1 or PD-L1, where the subject has previously been administered cyclophosphamide.
Cyclophosphamide and oxaliplatin administered prior to CAR T and PD-1/PD-L1 inhibitor
Administering to the subject cyclophosphamide, oxaliplatin or an active metabolite or derivative thereof, a T cell comprising a CAR that specifically binds to a ROR1 cell-surface antigen expressed by tumor cells, and an antibody or antigen-binding fragment that specifically binds to and is an inhibitor of PD-1 or PD-L1, wherein cyclophosphamide and oxaliplatin are administered prior to the CAR T and PD-1/PD-L1 inhibitor.
ROR1+ solid tumor treatment using oxaliplatin and cyclophosphamide with ROR1 CAR T and PD-1/PD-L1 inhibition
Treating a ROR1+ solid tumor in a subject by administering an effective amount of cyclophosphamide, an effective amount of oxaliplatin or an active metabolite or derivative thereof, an effective amount of a T cell comprising a heterologous CAR wherein the CAR comprises a single chain variable fragment (scFv) or a single chain fragment antigen-binding (scFab) specific for the ROR1, an extracellular hinge, a transmembrane component, and an intracellular component effector domain comprising a 4-1BB costimulatory domain and a CD32 domain, and an effective amount of an antibody or antigen binding fragment that specifically binds to and is an inhibitor of PD-1 or PD-L1, wherein the T cell comprises a CD8+ T cell and a CD4+ T cell.
Overall, the independent claims converge on a combination regimen for solid tumor treatment: ROR1-targeted CAR T cells together with PD-1/PD-L1 inhibitory antibody or antigen-binding fragments, with oxaliplatin and cyclophosphamide administered prior to or in temporal sequence relative to the CAR T and checkpoint inhibitor.
Stated Advantages
Synergistically improves tumor control when immunogenic cell death-inducing chemotherapy with oxaliplatin plus cyclophosphamide is combined with anti-PD-L1 and anti-ROR1 CAR T therapy.
Increases intratumoral CD3/CD8 infiltration.
Associates with changes in the immunosuppressive tumor microenvironment, including effects related to Tregs and MDSCs.
PD-1 blockade alone does not improve anti-tumor efficacy in the described context.
Documented Applications
Treating a solid tumor in a subject using ROR1-targeting CAR T cells combined with PD-1/PD-L1 inhibitory antibody or antigen-binding fragments and prior oxaliplatin and cyclophosphamide administration.
Treating a ROR1+ solid tumor in a subject using cyclophosphamide, oxaliplatin or active metabolite or derivative, ROR1 CAR T cells, and a PD-1/PD-L1 inhibitory antibody or antigen-binding fragment.
Preclinical mouse-model application in a KP mouse model of NSCLC expressing ROR1, using anti-ROR1 CAR T cells and immunogenic cell death-inducing chemotherapy plus PD-1/PD-L1 inhibition to evaluate tumor control and tumor microenvironment changes.
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