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However, most, if not all adoptive immunotherapy strategies require T cell activation and expansion steps to generate a clinically effective, therapeutic dose of T cells. 3. The method of claim 1, wherein activation of the T cells comprises contacting the T cells with an anti-CD3 antibody or CD3-binding fragment thereof. 18. The method of claim 16, wherein the PI3K inhibitor is a selective PI3K inhibitor selected from the group consisting of: BYL719, GSK2636771, TGX-221, AS25242, CAL-101, and IPI-145. 17. The method of claim 16, wherein the PI3K inhibitor is a pan-PI3K inhibitor selected from the group consisting of: BEZ235, LY294002, and GDC-0941. 9. The method of claim 8, wherein the extracellular domain comprises an antibody or antigen binding fragment that binds the antigen. 13. The method of claim 12, wherein the hinge region polypeptide comprises a hinge region of IgG1 or CD8.alpha.. 15. The method of claim 14, wherein the signal peptide comprises an IgG1 heavy chain signal polypeptide or a CD8.alpha.



14. The method of claim 8, further comprising a signal peptide. 6. The method of claim 1, wherein the viral vector is a lentiviral vector. Li, et al., "Optimal promoter usage for lentiviral vector-mediated transduction of cultured central nervous system cells." Journal of Neuroscience Methods (2010); 189 (1): Camera Websex 56-64. cited by applicant . While not wishing to be bound by any theory, the DNA flap may act as a cis-active determinant of lentiviral genome nuclear import and/or may increase the titer of the virus. In particular embodiments, promoters operative in mammalian cells comprise an AT-rich region located approximately 25 to 30 bases upstream from the site where transcription is initiated and/or another sequence found 70 to 80 bases upstream from the start of transcription, a CNCAAT region where N may be any nucleotide. For example, T cell expansion often requires labor intensive and expensive cloning, and/or multiple rounds of activation/expansion to achieve therapeutically relevant T cell numbers.



Perkins, et al., "Manufacturing an Enhanced Cart Cell Product by Inhibition of the PI3K/Akt Pathway During T Cell Expansion Results in Improved In Vivo Efficacy of Anti-BCMA CAR T Cells." Blood (2015); 126(3): 1893. cited by applicant . Halene, et al., "Improved Expression in Hematopoietic and Lymphoid Cells in Mice After Transplantation of Bone Marrow Transduced With a Modified Retroviral Vector." Blood (1999); 94(10): 3349-3357. cited by applicant . Uchibori, et al., "CD269 (BCMA)-Specific Car-Expressing T Cells Dramatically Eradicate Myeloma Cells from Bone Marrow of an Orthotopic Multiple Myeloma Mouse Model." Molecular Therapy (2016); Abstract 400, 24 (Supplement 1): p. Adoptive immunotherapy is the transfer of T lymphocytes to a subject for the therapy of disease. Wang, et al., "CS-1 Re-Directed Central Memory T Cell Therapy for Multiple Myeloma." Blood (2014); 124 (21): 1114. cited by applicant . Garfall, A.L., "Immunotherapy with Chimeric Antigen Receptors for Multiple Myeloma." Discovery Medicine: Discovery Class of Medicine, Research Technology, and T. Solariz, Inc., (2014); 17(91) 37-46. cited by applicant .