Cell-based anti-cancer compositions with reduced toxicity and methods of making and using the same
Isolated pluralities of T cells which recognize at least one epitope of an intestinal cancer antigen or CNS cancer antigen and pharmaceutical compositions comprising the same are disclosed. Methods of making a plurality of T cells that recognize at least one epitope of an intestinal cancer antigen or CNS cancer antigen are also disclosed. Methods of treating an individual who has been diagnosed with cancer of a mucosal tissue or preventing such cancer in an individual at elevated risk are disclosed as are nucleic acid molecules that comprise a nucleotide sequence that encode proteins that recognize at least one epitope of an intestinal cancer antigen or CNS cancer antigen and T cells comprising such nucleic acid molecules.
1. A plurality of T cells which recognize at least one epitope of guanylyl cyclase C and which are modified to inhibit expression or activity of α 4 β 7 integrin and chemokine receptor 9 (CCR9); wherein said T cells are derived from T cells isolated from an individual and transformed with a nucleic acid molecule which encodes a chimeric antigen receptor which binds to guanylyl cyclase C.
2. The plurality of T cells of claim 1 wherein the chimeric antigen receptor that binds to guanylyl cyclase C comprises:
a GCC specific scFv linked to a truncated CD28 extracellular domain to the intracellular part of the FcRIγ chain;
a GCC specific scFv linked to a truncated CD28 extracellular domain to the intracellular part of the CD3zeta signaling chain;
a GCC specific scFv linked to the intracellular part of the FcRIγ chain; or
a GCC specific scFv linked to the intracellular part of the CD3zeta signaling chain.
3. The plurality of T cells of claim 2 wherein the chimeric antigen receptor that binds to guanylyl cyclase C comprises a GCC specific scFv linked to a truncated CD28 extracellular domain to the intracellular part of the CD3zeta signaling chain.
4. The plurality of T cells of claim 1 , wherein the plurality of T cells are modified to inhibit expression of α 4 β 7 integrin by providing the plurality of T cells with nucleic acid sequences selected from the group consisting of: nucleic acid sequences that express siRNA which inhibits expression of α 4 β 7 integrin, nucleic acid sequences that express microRNA which inhibits expression of α 4 β 7 integrin, and nucleic acid sequences that express antisense sequences which inhibit expression of α 4 β 7 integrin and modified to inhibit expression of CCR9 by providing the plurality of T cells with nucleic acid sequences selected from the group consisting of: nucleic acid sequences that express siRNA which inhibits expression of CCR9, nucleic acid sequences that express microRNA which inhibits expression of CCR9, and nucleic acid sequences that express antisense sequences which inhibit expression of CCR9.
5. The plurality of T cells of claim 4 , wherein the plurality of T cells are modified to inhibit expression of α 4 β 7 integrin and CCR9 by providing the plurality of T cells with nucleic acid sequences that express siRNA which inhibits expression of α 4 β 7 integrin and nucleic acid sequences that express siRNA which inhibits expression of CCR9.
6. The plurality of T cells of claim 5 wherein the chimeric antigen receptor that binds to guanylyl cyclase C comprises a GCC specific scFv linked to a truncated CD28 extracellular domain to the intracellular part of the CD3zeta signaling chain.
7. A pharmaceutical composition comprising an isolated the plurality of T cells of claim 1 and a pharmaceutically acceptable carrier or diluent.
8. A method of treating an individual who has been diagnosed with cancer that expresses guanylyl cyclase C comprising the step of administering to the individual an effective amount of a plurality of T cells of claim 1 .