Methods and compositions for adoptive cell therapy

Abstract

Provided are methods for multiple administrations of cells for adoptive cell therapy, and for administering cells to subjects having received prior administrations, and compositions and articles of manufacture for use in the methods. The cells generally express recombinant molecules such as recombinant receptors, e.g., chimeric antigen receptors (CARs) and/or other transgenic receptors. The methods can involve administering cells expressing a first or prior receptor(s) and cells expressing a second or subsequent receptor(s), the second or subsequent receptor(s) being distinct from the first, and which generally do not express the first receptor, and/or administering the cells expressing the second receptor to a subject having received the first administration. The methods can provide various advantages, such as improved efficacy in the context an immune response in the subject against the first or prior receptor and/or in the context of antigen loss, downregulation, or modification, following a first or prior administration.

1 - 91 . (canceled) 
     
     
         92 . A method of treatment, comprising administering cells expressing a second chimeric antigen receptor (CAR) to a subject that has previously received an administration of cells expressing a first CAR, wherein:
 the first CAR specifically binds to an antigen associated with the B cell malignancy;   the second CAR, which is distinct from the first CAR, specifically binds to the antigen specifically bound by the first CAR or a different antigen associated with the B cell malignancy; and   the second CAR comprises at least one region identical in amino acid sequence to a corresponding region of the first CAR.   
     
     
         93 . A method of treatment, comprising administering cells expressing a second chimeric antigen receptor (CAR) to a subject that has previously received an administration of cells expressing a first CAR, wherein:
 the first CAR specifically binds to an antigen associated with the B cell malignancy;   the second CAR, which is distinct from the first CAR, specifically binds to the antigen specifically bound by the first CAR or a different antigen associated with the B cell malignancy; and   wherein the cells expressing the second CAR is administered at least about 28 days following administration of cells expressing the first CAR.   
     
     
         94 . A method of treatment, comprising administering cells expressing a second chimeric antigen receptor (CAR) to a subject that has previously received an administration of cells expressing a first CAR, wherein:
 the first CAR specifically binds to an antigen associated with the B cell malignancy;   the second CAR, which is distinct from the first CAR, specifically binds to the antigen specifically bound by the first CAR or a different antigen associated with the B cell malignancy; and   wherein the B cell malignancy has relapsed or persists in the subject following administration of cells expressing the first CAR.   
     
     
         95 . A method of treatment, comprising administering cells expressing a second chimeric antigen receptor (CAR) to a subject that has previously received an administration of cells expressing a first CAR, wherein:
 the first CAR specifically binds to CD19; and   the second CAR, which is distinct from the first CAR, specifically binds to CD22.   
     
     
         96 . The method of  claim 92 , wherein the first CAR specifically binds to an antigen selected from CD19, CD22 or CD20 and the second CAR binds to another antigen from among CD19, CD22 or CD20 that is distinct from the antigen bound by the first CAR. 
     
     
         97 . The method of  claim 93 , wherein the first CAR specifically binds to an antigen selected from CD19, CD22 or CD20 and the second CAR binds to another antigen from among CD19, CD22 or CD20 that is distinct from the antigen bound by the first CAR. 
     
     
         98 . The method of  claim 94 , wherein the first CAR specifically binds to an antigen selected from CD19, CD22 or CD20 and the second CAR binds to another antigen from among CD19, CD22 or CD20 that is distinct from the antigen bound by the first CAR. 
     
     
         99 . The method of  claim 92 , wherein the composition is for administration at least about 28 days following administration of cells expressing the first CAR. 
     
     
         100 . The method of  claim 94 , wherein the composition is for administration at least about 28 days following administration of cells expressing the first CAR. 
     
     
         101 . The method of  claim 94 , wherein the second CAR comprises at least one region identical in amino acid sequence to a corresponding region of the first CAR. 
     
     
         102 . The method of  claim 92 , wherein the B cell malignancy is a lymphoma or leukemia. 
     
     
         103 . The method of  claim 93 , wherein the B cell malignancy is a lymphoma or leukemia. 
     
     
         104 . The method of  claim 94 , wherein the B cell malignancy is a lymphoma or leukemia. 
     
     
         105 . The method of  claim 95 , wherein the B cell malignancy is a lymphoma or leukemia. 
     
     
         106 . The method of  claim 92 , wherein:
 a) cells expressing the second CAR comprise from or from about 1×10 6  to about 1×10 8  of the CAR-expressing cells, T cells or peripheral blood mononuclear cells (PBMCs); or   b) cells expressing the second CAR comprise more than about 1×10 6  CAR-expressing cells, T cells or PBMCs per kilogram body weight of the subject.   
     
     
         107 . The method of  claim 93 , wherein:
 a) cells expressing the second CAR comprise from or from about 1×10 6  to about 1×10 8  of the CAR-expressing cells, T cells or peripheral blood mononuclear cells (PBMCs); or   b) cells expressing the second CAR comprise more than about 1×10 6  CAR-expressing cells, T cells or PBMCs per kilogram body weight of the subject.   
     
     
         108 . The method of  claim 94 , wherein:
 a) cells expressing the second CAR comprise from or from about 1×10 6  to about 1×10 8  of the CAR-expressing cells, T cells or peripheral blood mononuclear cells (PBMCs); or   b) cells expressing the second CAR comprise more than about 1×10 6  CAR-expressing cells, T cells or PBMCs per kilogram body weight of the subject.   
     
     
         109 . The method of  claim 95 , wherein:
 a) cells expressing the second CAR comprise from or from about 1×10 6  to about 1×10 8  of the CAR-expressing cells, T cells or peripheral blood mononuclear cells (PBMCs); or   b) cells expressing the second CAR comprise more than about 1×10 6  CAR-expressing cells, T cells or PBMCs per kilogram body weight of the subject.   
     
     
         110 . The method of  claim 92 , wherein the at least one region identical in sequence is selected from the group consisting of an intracellular costimulatory signaling domain, an immunoreceptor tyrosine-based activation motif (ITAM)-containing domain, and a transmembrane domain. 
     
     
         111 . The method of  claim 101 , wherein the at least one region identical in sequence is selected from the group consisting of an intracellular costimulatory signaling domain, an immunoreceptor tyrosine-based activation motif (ITAM)-containing domain, and a transmembrane domain. 
     
     
         112 . The method of  claim 92 , wherein the cells expressing the first CAR are T cells, and/or the cells expressing the second CAR are T cells. 
     
     
         113 . The method of  claim 93 , wherein the cells expressing the first CAR are T cells, and/or the cells expressing the second CAR are T cells. 
     
     
         114 . The method of  claim 94 , wherein the cells expressing the first CAR are T cells, and/or the cells expressing the second CAR are T cells. 
     
     
         115 . The method of  claim 95 , wherein the cells expressing the first CAR are T cells, and/or the cells expressing the second CAR are T cells.