The present invention relates to a Leukocyte-specific protein 1 (LSP1)-deficient T cell-based anticancer immunotherapy. According to the present invention, tumor growth, tumor volume and size were reduced by means of LSP1 knockout, and LSP1 deficiency in T cells increases the number, distribution frequency, migration, and invasion of T cells, and increases the production of an anti-tumor cytokine to inhibit tumor growth and enhance tumor-killing ability. Thus, the present invention can be used for T cell-based immunotherapy.

Provided is an isolated or purified T cell comprising an antigen-specific receptor, wherein the antigen-specific receptor is a T cell receptor (TCR) or a chimeric antigen receptor (CAR), wherein the T cell has been modified to express a transcription factor at a level that is higher than the level of the transcription factor expressed by a T cell that has not been modified to express the transcription factor, wherein the transcription factor is V-Myb Avian Myeloblastosis Viral Oncogene Homolog (c-Myb), a functional variant of c-Myb, or a functional fragment of c-Myb. Related populations of cells, pharmaceutical compositions, methods of treating a disease, and methods of inhibiting the differentiation of T cells are also provided.

Tumor infiltrating lymphocytes (TILs) are white blood cells that are actively recruited to the tumor site to mount an immune response against tumor growth and metastasis. The disclosure provides methods for treating cancer that comprise steps of isolating CD8+ T cells from a sample derived from a subject, expanding the CD8+ T cells in the presence of interleukin-10, and administering the expanded CD8+ T cells to the subject. Methods of treating cancer may be used in combination with inhibitors of the complement signaling pathway.

Embodiments of the disclosure include methods and compositions related to chimeric antigen receptors (CAR) that target chondroitin sulfate proteoglycan-4 (CSPG4). T cells transduced with a CSPG4-specific CAR are effective for inhibition of particular cancer cells that express CSPG4. In certain embodiments, the cancer is melanoma, breast cancer, head and neck cancer, mesothelioma, glioblastoma, or renal cancer.

Pre-conditioning a vaccine site with a potent recall antigen such as tetanus/diphtheria (Td) toxoid can significantly improve the lymph node homing and efficacy of tumor antigen-specific DC vaccines. Patients given Td had enhanced DC migration bilaterally and significantly improved survival. In mice, Td pre-conditioning also enhanced bilateral DC migration and suppressed tumor growth in a manner dependent on the chemokines CCL3 and CCL21 and Td-activated CD4.sup.+ T cells. Interference with any component of this axis markedly reduced Td-mediated DC migration and antitumor responses. Our clinical studies and corroborating investigations in mice suggest that pre-conditioning with a potent recall antigen represents a viable strategy to increase DC homing to lymph nodes and improve antitumor immunotherapy.

The success of anti-tumor immune responses requires effector T cells to infiltrate solid tumors, a process guided by chemokines. Herein, we demonstrate that in vivo post-translational processing of chemokines by dipeptidylpeptidase 4 (DPP4, also known as CD26) limits lymphocyte migration to sites of inflammation and tumors. Inhibition of DPP4 enzymatic activity enhanced tumor rejection by preserving biologically active CXCL10, and increasing trafficking into the tumor by lymphocytes expressing the counter-receptor CXCR3. Furthermore, DPP4 inhibition improved adjuvant-based immunotherapy, adoptive T cell transfer and checkpoint blockade. These findings provide the first direct in vivo evidence for controlling lymphocyte trafficking through CXCL10 cleavage and support the use of DPP4 inhibitors for stabilizing the biologically active form of chemokines as a strategy to enhance tumor immunotherapy.

The present invention relates to lymphocytes, preferably that have been transinfected from dendritic cells with a bacterium, preferably CD4.sup.+ T cells, preferably Listeria monocytogenes, wherein said bacterium comprises a tumor peptide. It also relates to the use of lymphocytes for therapy and/or treatment of solid tumors, preferably melanoma, the kit or device which comprises for this purpose. Furthermore, it also refers to the transinfection method thereof.

The present invention provides methods for increasing expression of at least one co-stimulatory and/or co-inhibitory receptor on a T cell comprising contacting said T cell with an anti-CTLA4 antibody. In one aspect the co-stimulatory and/or co-inhibitory receptor is selected from the group of: PD-1, OX40, ICOS, CD137, TIM3, and LAG3. The present invention also provides methods of treating cancer in a human in need thereof comprising administering an anti-CTLA antibody and at least one additional agent directed to at least one co-stimulatory and/or co-inhibitory receptor to said human. In one aspect, the agent is directed to at least one co-stimulatory and/or co-inhibitory receptor selected from the group of: PD-1, OX40, ICOS, CD137 (4-1BB), TIM3, and LAG3.

The present disclosure provides methods for re-stimulating TIL populations that lead to improved phenotype and increased metabolic health of the TILs and provides methods of assaying for TIL populations to determine suitability for more efficacious infusion after re-stimulation.

This invention relates to the field of therapeutics. Most specifically invention provides methods of generating in vitro engineered immune cells conditionally expressing interleukin-12 (IL-12) and one or more immunomodulators under the control of a gene expression modulation system in the presence of activating ligand and uses for therapeutic purposes in animals.