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Responsibility: ed. By Ainley Wade and Paul J.

The composition for use or the method of any of the preceding claims, wherein the immune effector cell to be engineered to express a CAR, is harvested after a sufficient time, or after sufficient dosing of the mTOR inhibitor, such that the level of PDl negative immune effector cells which are optionally T cells, or the ratio of PDl negative immune effector cells, which are optionally T cells/ PDl positive immune effector cells, which are optionally T cells, in the subject or harvested from the subject has been, at least transiently, increased. COMBINATIONS OF LOW, IMMUNE ENHANCING, DOSES OF MTOR INHIBITORS AND CARs RELATED APPLICATIONS [001] This application claims priority to U.S. 62/027152 filed July 21, 2014, U.S.

62/076197 filed Nov 6, 2014, and U.S. 62/164357 filed May 20, 2015, the contents of which are incorporated herein by reference in their entireties.

Call Recorder For Nokia 2730 Classic Free Download. SEQUENCE LISTING [002] The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on July 21, 2015, is named N2067-7065WO_SL.txt and is 169,256 bytes in size.

FIELD OF THE INVENTION [003] The invention relates generally to the administration of a low, immune enhancing dose of an mTOR inhibitor in combination with immune effector cells (e.g., T cells or NK cells) engineered to express a Chimeric Antigen Receptor (CAR) to treat a disease, e.g., a disease associated with expression of a tumor marker. BACKGROUND [004] Functional and effective T-cell responses play an important role in effective immune responses, for example, against infectious diseases and cancer. However, under certain conditions, such as chronic infection or cancer, effector T cells can be suppressed by various immunosuppressive mechanisms, including (PD-Ll)/programmed death- 1 (PD-1) interaction, leading to T-cell exhaustion (Pen et al. Gene Therapy 21, 262-271, 2014).

It is thought that programmed death ligand-1 PD-L1 is normally expressed by most cell types, while its receptor PD-1 is only present on certain immune cells, such as activated T cells and regulatory T (Treg) cells. It is also thought that PD-Ll/PD-1 binding is important in the maintenance of peripheral T-cell tolerance, preventing autoimmune responses. On the other hand, high levels of PD-1 expression generally correlate with loss of T cell function, leading to increased viral load in cases of viral infection (Pen et al.

Gene Therapy 21, 262-271, 2014). SUMMARY OF THE INVENTION [005] Methods and compositions disclosed herein are directed to the administration of a low, immune enhancing dose of an mTOR inhibitor and immune effector cells (e.g., T cells or NK cells) engineered to express a Chimeric Antigen Receptor (CAR), to treat a disease, e.g., a disease associated with expression of a cancer associated antigen (or tumor marker). [006] It has been discovered that partial mTOR inhibition, e.g., with low, immune enhancing, doses of an mTOR inhibitor, e.g., an allosteric mTOR inhibitor, such as RAD001, is effective in improving immune function in a subject, and can be combined with CAR therapy to treat the subject. While not wishing to be bound by theory, it is believed that treatment with a low, immune enhancing, dose (e.g., a dose that is insufficient to completely suppress the immune system but sufficient to improve immune function) of an mTOR inhibitor is accompanied by a decrease in PD-1 positive T cells or an increase in PD-1 negative cells. PD-1 positive T cells, but not PD-1 negative T cells, can be exhausted by engagement with cells which express a PD-1 ligand, e.g., PD-L1 or PD-L2.

In addition or alternatively, again without wishing to be bound by theory, it is believed that treatment with a low, immune enhancing, dose of an mTOR inhibitor can increase naive T cell numbers, e.g., at least transiently, e.g., as compared to a non-treated subject. [00274] Everolimus is an FDA approved drug for the treatment of advanced kidney cancer and is being investigated in several other phase III clinical trials in oncology. Preclinical studies have shown that Everolimus is able to inhibit the proliferation of a wide variety of tumor cell lines both in vitro and in vivo, presumably through the suppression of rapamycin sensitive mTORCl function.

Everolimus, as a derivative of rapamycin, is an allosteric mTOR inhibitor that is highly potent at inhibiting part of the mTORCl function, namely P70 S6 kinase (P70 S6K) and the downstream P70 S6K substrate P70 S6. Allosteric mTOR inhibitors like everolimus (and other rapamycin analogs) have little or no effect at inhibiting the mTORC2 pathway, or its resulting activation of Akt signaling. Further examples of allosteric mTOR inhibitors include sirolimus (rapamycin, AY-22989), 40-[3-hydroxy-2-(hydroxymethyl)-2- methylpropanoate] -rapamycin (also called temsirolimus or CCT779) and ridaforolimus (AP- 23573/MK-8669).

Other examples of allosteric mTor inhibtors include zotarolimus (ABT578) and umirolimus. [00275] Alternatively or additionally, catalytic, ATP-competitive mTOR inhibitors have been found to target the mTOR kinase domain directly and target both mTORCl and mTORC2. These are also more effective inhibitors of mTORCl than such allosteric mTOR inhibitors as rapamycin, because they modulate rapamycin-resistant mTORCl outputs such as 4EBP1-T37/46 phosphorylation and cap-dependent translation.

[00276] BEZ235 is a catalytic mTOR inhibitor, having the chemical name 2-methyl-2-[4-(3- methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-l-yl)-phenyl]-propionitrile and the following chemical structure. [00568] Other suitable dimerization switches include a GyrB-GyrB based dimerization switch, a Gibberellin-based dimerization switch, a tag/binder dimerization switch, and a halo-tag/snap- tag dimerization switch. Following the guidance provided herein, such switches and relevant dimerization molecules will be apparent to one of ordinary skill.

Dimerization molecule [00569] Association between the switch domains is promoted by the dimerization molecule. In the presence of dimerization molecule interaction or association between switch domains allows for signal transduction between a polypeptide associated with, e.g., fused to, a first switch domain, and a polypeptide associated with, e.g., fused to, a second switch domain. In the presence of non-limiting levels of dimerization molecule signal transduction is increased by 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 5, 10, 50, 100 fold, e.g., as measured in a system described herein. [00570] Rapamycin and rapamycin analogs (sometimes referred to as rapalogues), e.g., RAD001, can be used as dimerization molecules in a FKBP/FRB-based dimerization switch described herein. In an embodiment the dimerization molecule can be selected from rapamycin (sirolimus), RAD001 (everolimus), zotarolimus, temsirolimus, AP-23573 (ridaforolimus), biolimus and AP21967. Additional rapamycin analogs suitable for use with FKBP/FRB-based dimerization switches are further described in the section entitled 'Combination Therapies', or in the subsection entitled 'mTOR inhibitors'.

Split CAR In some embodiments, the CAR-expressing cell uses a split CAR. The split CAR approach is described in more detail in publications WO2014/055442 and WO2014/055657.

Briefly, a split CAR system comprises a cell expressing a first CAR having a first antigen binding domain and a costimulatory domain (e.g., 4- IBB), and the cell also expresses a second CAR having a second antigen binding domain and an intracellular signaling domain (e.g., CD3 zeta). When the cell encounters the first antigen, the costimulatory domain is activated, and the cell proliferates. When the cell encounters the second antigen, the intracellular signaling domain is activated and cell-killing activity begins. Thus, the CAR-expressing cell is only fully activated in the presence of both antigens.