Methods and compositions for dosing in adoptive cell therapy

Abstract

Provided are methods for administering multiple doses of cells, such as T cells, to subjects for cell therapy. Also provided are compositions and articles of manufacture for use in the methods. The cells generally express recombinant receptors such as chimeric receptors, e.g., chimeric antigen receptors (CARs) or other transgenic receptors such as T cell receptors (TCRs). The methods generally involve administering a first and at least one consecutive dose of the cells. Timing of the doses relative to one another, and/or size of the doses, in some embodiments provide various advantages such as lower or reduced toxicity and improved efficacy, for example, due to increased exposure of the subject to the administered cells. In some embodiments, the first dose is a relatively low dose, such as one that reduces tumor or disease burden, thereby improving the efficacy of consecutive or subsequent doses, and the consecutive dose is a consolidating dose.

1 . A method of treatment, comprising:
 administering a consecutive dose of T cells expressing a chimeric antigen receptor (CAR) to a subject having a disease or condition and having been previously administered a first dose of T cells expressing a CAR, wherein:   (i) the first dose is from 1×10 6  cells per kilogram to 1×10 8  cells per kilogram body weight of the subject, from 1×10 6  cells/m 2  to 1×10 7  cells/m 2 , or from 5×10 7  of cells to 5×10 8  cells; and   (ii) the CAR expressed by the cells in the first dose and the CAR expressed by the cells of the consecutive dose each, individually, binds to an antigen expressed by a cell or tissue of the disease or condition or associated with the disease or condition.   
     
     
         2 . The method of  claim 1 , wherein the disease or condition persists in the subject following the administration of the first dose. 
     
     
         3 . The method of  claim 1 , wherein the CAR expressed by the cells in the consecutive dose is identical to the CAR expressed by the cells in the first dose or is substantially identical to the CAR expressed by the cells in the first dose. 
     
     
         4 . The method of  claim 1 , wherein the CAR expressed by the cells in the consecutive dose is different to the CAR expressed by the cells in the first dose. 
     
     
         5 . The method of  claim 1 , wherein the CAR expressed by the cells in the consecutive dose targets the same antigen as the CAR expressed by the cells in the first dose. 
     
     
         6 . The method of  claim 1 , wherein the cells of the consecutive dose are autologous to the subject. 
     
     
         7 . The method of  claim 1 , wherein the cells of the consecutive dose are allogeneic to the subject. 
     
     
         8 . The method of  claim 6 , wherein the cells of the first dose are autologous to the subject or allogeneic to the subject. 
     
     
         9 . The method of  claim 7 , wherein the cells of the first dose are autologous to the subject or allogeneic to the subject. 
     
     
         10 . The method of  claim 1 , wherein the consecutive dose comprises the same or substantially similar number of cells as the first dose. 
     
     
         11 . The method of  claim 1 , wherein the first dose of cells is from 1×10 6  cells per kilogram to 1×10 8  cells per kilogram body weight of the subject. 
     
     
         12 . The method of  claim 1 , wherein the first dose is from 1×10 6  cells/m 2  to 1×10 7  cells/m 2 . 
     
     
         13 . The method of  claim 1 , wherein the first dose is from 5×10 7  of cells to 5×10 8  cells. 
     
     
         14 . The method of  claim 1 , wherein the disease or condition is a tumor or cancer. 
     
     
         15 . The method of  claim 1 , wherein the disease or condition is a B cell malignancy. 
     
     
         16 . The method of  claim 1 , wherein the disease or condition is a leukemia or lymphoma. 
     
     
         17 . The method of  claim 1 , wherein the disease or condition is acute lymphoblastic leukemia or non-Hodgkin lymphoma (NHL). 
     
     
         18 . The method of  claim 1 , wherein the antigen is CD19, CD20, CD22 or ROR1. 
     
     
         19 . The method of  claim 1 , wherein the subject exhibits detectable molecular disease and/or minimum residual disease at a time just prior to the administration of the consecutive dose of cells. 
     
     
         20 . The method of  claim 1 , wherein the method comprises:
 i) assessing a factor indicative of disease after administration of the first dose of cells and prior to administration of the consecutive dose of cells;   ii) based on the result of the assessment, determining the consecutive dose of cells to be administered to the subject, and   iii) if the assessment determines that the subject has morphologic disease, administering to the subject a consecutive dose comprising less than or about the same number of CAR-expressing cells as the number of CAR-expressing cells in the first dose; and if the assessment determines that the subject has minimal residual disease, administering to the subject a consecutive dose comprising an increased number of CAR-expressing cells as compared to the first dose.   
     
     
         21 . The method of  claim 1 , wherein:
 if at a time just prior to initiation of administration of the consecutive dose of cells the subject exhibits or is suspected of exhibiting morphologic disease, the consecutive dose comprises less than or about the same number of CAR-expressing cells as the number of CAR-expressing cells in the first dose; and   if at a time just prior to initiation of administration of the consecutive dose of cells the subject exhibits or is suspected of exhibiting minimum residual disease, the consecutive dose comprises an increased number of CAR-expressing cells as compared to the first dose.   
     
     
         22 . The method of  claim 1 , further comprising administering a chemotherapeutic agent prior to the administration of the consecutive dose of cells. 
     
     
         23 . The method of  claim 1 , wherein the subject has been previously treated with a chemotherapeutic agent prior to administration of the first dose and/or prior to the administration of the consecutive dose. 
     
     
         24 . The method of  claim 22 , wherein the chemotherapeutic agent comprises an agent selected from the group consisting of cyclophosphamide and fludarabine. 
     
     
         25 . The method of  claim 22 , wherein the chemotherapeutic agent comprises a combination of cyclophosphamide and fludarabine. 
     
     
         26 . The method of  claim 23 , wherein the chemotherapeutic agent comprises an agent selected from the group consisting of cyclophosphamide and fludarabine. 
     
     
         27 . The method of  claim 23 , wherein the chemotherapeutic agent comprises a combination of cyclophosphamide and fludarabine. 
     
     
         28 . The method of  claim 1 , wherein the CAR of the consecutive dose of cells comprises an intracellular domain comprising a CD3zeta signaling domain. 
     
     
         29 . The method of  claim 1 , wherein the CAR of the consecutive dose of cells comprises an intracellular domain comprising a 4-1BB costimulatory signaling domain and a CD3zeta signaling domain. 
     
     
         30 . The method of  claim 1 , wherein the CAR of the consecutive dose of cells comprises a CD8 transmembrane domain and a CD3zeta signaling domain.