Phenotypic markers for cell therapy and related methods
Provided are methods, compositions and articles of manufacture for use in cell therapy involving the administration of one or more doses of a therapeutic T cell composition, and methods, compositions and articles of manufacture for use in the same. The cells of the T cell composition express recombinant receptors such as chimeric receptors, e.g. chimeric antigen receptors (CARs) or other transgenic receptors such as T cell receptors (TCRs). Features of the embodiments of the present disclosure, including the dose of cells or units of cells administered and/or the phenotype of administered cells, provide various advantages, such as consistent dosing, lower risk of toxicity and/or increased response in subjects administered the T cell compositions.
1. A method of treatment, the method comprising administering to a subject having lymphoma or leukemia a unit dose of a therapeutic composition comprising a plurality of CD8 + and/or CD4 + T cells engineered to express a recombinant receptor, wherein the recombinant receptor is a chimeric antigen receptor directed to CD19, wherein:
the plurality of CD8+ and/or CD4+ T cells have been isolated from the peripheral blood of the subject and engineered with the recombinant receptor; and
the unit dose of cells comprises between 1×10 5 and 1×10 8 total recombinant receptor-expressing CD8 + T cells that express CD27 and CCR7 (receptor + /CD8 + /CCR7 + /CD27 + T cells) and/or recombinant receptor-expressing CD4 + T cells that express CCR7 and CD27 (receptor + /CD4 + /CCR7 + /CD27 + T cells).
2. The method of claim 1 , wherein the T cells expressing the recombinant receptor that are surface positive for CD27 and CCR7 are also surface negative for CD45RA.
3. The method of claim 1 , wherein at least 15% of the total receptor + T cells in the composition are receptor + /CD8 + /CCR7 + /CD27 + or receptor + /CD4 + /CCR7 + /CD27 + .
4. The method of claim 1 , wherein, prior to the administering, the method further comprises assaying the therapeutic composition comprising a plurality of CD8 + and/or CD4 + T cells engineered to express a recombinant receptor for the percentage of T cells expressing the recombinant receptor that are surface positive for CD27 and CCR7.
5. The method of claim 1 , wherein the unit dose comprises between 3×10 6 and 2.5×10 7 total receptor + /CD8 + /CCR7 + /CD27 + viable T cells and/or between 3×10 6 and 2.5×10 7 total receptor + /CD4 + /CCR7 + /CD27 + viable T cells, each inclusive.
6. The method of claim 1 , wherein between 15% and 90% of the total receptor + T cells in the unit dose are receptor + /CD8 + /CCR7 + /CD27 + or receptor + /CD4 + /CCR7 + /CD27 + , each inclusive.
7. The method of claim 1 , wherein the defined ratio of receptor*/CD8+/CCR7+/CD27+ T cells to receptor*/CD4+/CCR7+/CD27+ T cells is between 1:3 and 3:1.
8. The method of claim 1 , wherein the unit dose of cells is administered as a plurality of unit doses contained in separate compositions.
9. The method of claim 8 , wherein the separate compositions comprise a first composition comprising one of the CD8 + T cells and the CD4 + T cells and a second composition comprising the other of the CD8 + T cells and the CD4 + T cells.
10. A method for treatment of a subject, the method comprising: (A) assaying an engineered cell composition comprising T cells expressing a recombinant receptor for the percentage of T cells expressing the recombinant receptor that are surface positive for a phenotype that is CD27 and CCR7, wherein the recombinant receptor is a chimeric antigen receptor directed to CD 19, and wherein the T cells have been isolated from the peripheral blood of the subject and engineered with the chimeric antigen receptor; and (B) administering to a subject having lymphoma or leukemia a therapy, the administering selected from: (1) if the percentage of T cells surface positive for the phenotype of cells of the engineered T cell composition is at or above a threshold value, administering to the subject one or more unit doses of cells of the engineered cell composition comprising T cells expressing the recombinant receptor that are surface positive for the phenotype; or (2) if the percentage of T cells surface positive for the phenotype of cells of the engineered T cell composition is below a threshold value, administering a therapy selected from (a) one or more unit doses of cells of the engineered cell composition and an agent capable of increasing expansion, proliferation or efficacy of T cells of the engineered cell composition in the subject, or (b) an increased dose of cells of the engineered cell composition; wherein the threshold value of the percentage of T cells surface positive for the phenotype is about 15 percent of the total number of T cells in the composition or of the total number of T cells in the composition expressing the recombinant receptor that are surface positive for CD27 and CCR7.
11. The method of claim 10 , wherein the unit dose comprises between 3×10 6 and 2.5×10 7 total receptor + /CD8 + /CCR7 + /CD27 + viable T cells and/or between 3×10 6 and 2.5×10 7 total receptor + /CD4 + /CCR7 + /CD27 + viable T cells, each inclusive.
12. The method of claim 10 , wherein between 15% and 90% of the total receptor + T cells in the unit dose are receptor + /CD8 + /CCR7 + /CD27 + or receptor + /CD4 + /CCR7 + /CD27 + , each inclusive.
13. The method of claim 10 , wherein the ratio of receptor*/CD8+/CCR7+/CD27+ T cells to receptor*/CD4+/CCR7+/CD27+ T cells is between 1:3 and 3:1.
14. The method of claim 10 , wherein the unit dose comprises between 1×10 5 and 5×10 8 total CD3 + viable T cells that express the recombinant receptor (receptor + /CD3 + cells) or total CD3 + viable T cells, each inclusive.
15. The method of claim 10 , wherein the unit dose of cells is administered as a plurality of unit doses contained in separate compositions.
16. The method of claim 15 , wherein the separate compositions comprise a first composition comprising one of the CD8 + T cells and the CD4 + T cells and a second composition comprising the other of the CD8 + T cells and the CD4 + T cells.
17. A method of treatment, the method comprising administering to a subject having lymphoma or leukemia a unit dose of a therapeutic composition comprising a plurality of CD8 + and/or CD4 + T cells engineered to express a recombinant receptor, wherein:
the plurality of CD8+ and/or CD4+ T cells have been isolated from the peripheral blood of the subject and engineered with the recombinant receptor; and
the unit dose of cells comprises between 3×10 6 and 2.5×10 7 recombinant receptor-expressing CD8 + T cells that express CD27 and CCR7 (receptor + /CD8 + /CCR7 + /CD27 + T cells) and/or recombinant receptor-expressing CD4 + T cells that express CCR7 and CD27 (receptor + /CD4 + /CCR7 + /CD27 + T cells).
18. The method of claim 17 , wherein at least 15% of the total receptor + cells in the unit dose are receptor + /CD8 + /CCR7 + /CD27 + or receptor + /CD4 + /CCR7 + /CD27 + .
19. The method of claim 17 , wherein between 15% and 90% of the total receptor + cells in the unit dose are receptor + /CD8 + /CCR7 + /CD27 + or receptor + /CD4 + /CCR7 + /CD27 + , each inclusive.
20. The method of claim 17 , wherein the ratio of receptor*/CD8+/CCR7+/CD27+ T cells to receptor+/CD4+/CCR7+/CD27+ T cells is between 1:3 and 3:1.