The present disclosure relates to methods for profiling subject specific and personalized T cell receptor (TCR) repertoires using a single-cell sequencing method. More particularly, disclosed are methods for determining binding of T cell receptors to subject specific neoantigens. In addition, the techniques herein may identify the antigenic targets of T cell receptors in the context of tumor neoantigens. Moreover, the present disclosure enables the discovery of T cell targets in numerous diseases, with implications for understanding the basic mechanisms of the mammalian immune response and for developing antigen-specific diagnostic markers and therapies. Finally, cloned TCRs can be used to formulate personalized immunotherapies for those inflicted with a disease, such as cancer.

PD1-CD70 fusion proteins are provided. Accordingly, there is provided a PD1-CD70 fusion protein comprising a single amino acid linker between the PD1 and the CD70. Also there is provided a PD1-CD70 fusion protein, wherein the PD1 amino acid is 123-166 amino acids in length and/or wherein the PD1 amino acid sequence comprises SEQ ID NO: 2 and/or wherein the fusion protein is in a form of at least a homo-trimer. Also provided are polynucleotides and nucleic acid constructs encoding the PD1-CD70 fusion protein, host-cells expressing the PD1-CD70 fusion protein and methods of use thereof.

As described below, the present invention features genetically modified immune cells having enhanced anti-neoplasia activity, resistance to immune suppression, and decreased risk of eliciting a graft versus host reaction, or a combination thereof. The present invention also features methods for producing and using these modified immune effector cells.

PD1-41BBL fusion proteins are provided. Accordingly, there is provided a PD1-41BBL fusion protein comprising a single amino acid linker between the PD1 and the 41BBL. Also there is provided a PD1-41BBL fusion protein, wherein the PD1 amino acid is 123-166 amino acids in length and/or wherein the PD1 amino acid sequence comprises SEQ ID NO: 2 and/or wherein the fusion protein is in a form of at least a homo-trimer. Also provided are polynucleotides and nucleic acid constructs encoding the PD1-41BBL fusion protein, host-cells expressing the PD1-41BBL fusion protein and methods of use thereof.

T cells, notably CD8 T cells, are known to be essential players in tumor eradication as the presence of tumor-infiltrating lymphocytes (TILS) in several cancers positively correlates with a good prognosis. To eliminate tumor cells, CD8 T cells recognize tumor antigens, which are MHC I-associated peptides present at the surface of tumor cells, with no or very low expression on normal cells. Described herein a proteogenomic approach using RNA-sequencing data from cancer and normal-matched mTEC.sup.hi samples in order to identify non-tolerogenic tumor-specific antigens derived from (i) coding and non-coding regions of the genome, (ii) non-synonymous single-base mutations or short insertion/deletions and more complex rearrangements as well as (iii) endogenous retroelements, which works regardless of the sample's mutational load or complexity.

Genetically engineered T cells expressing a chimeric antigen receptor (CAR) that binds B-cell maturation antigen (BCMA) and uses thereof for treating multiple myeloma, for example, refractory and/or relapsed multiple myeloma. The genetically engineered T cells may comprise a disrupted endogenous TRAC gene and/or a disrupted endogenous β2M gene.

PD1-CD70 fusion proteins are provided. Accordingly, there is provided a PD1-CD70 fusion protein comprising a single amino acid linker between the PD1 and the CD70. Also there is provided a PD1-CD70 fusion protein, wherein the PD1 amino acid is 123-166 amino acids in length and/or wherein the PD1 amino acid sequence comprises SEQ ID NO: 2 and/or wherein the fusion protein is in a form of at least a homo-trimer. Also provided are polynucleotides and nucleic acid constructs encoding the PD1-CD70 fusion protein, host-cells expressing the PD1-CD70 fusion protein and methods of use thereof.

The present invention relates to new CD22 Chimeric Antigen Receptors (CD22 CAR), an engineered immune cell endowed with said new CD22 CAR and comprising at least inactivated TRAC gene for use in therapy. The engineered immune cells endowed with such CARs are particularly suited for treating relapsed refractory CD22 expressing cancers.

Provided herein are CD70 targeting chimeric antigen receptors and engineered immune cells (e.g., T cells) comprising such CAR. Method of treating a cancer expressing CD70 using such engineered immune cells are also provided. In some embodiments, the method of treating cancer further comprising using an agent that enhances CD70 expression in the cancer (e.g., azacitidine) in combination with the engineered immune cells comprising the CD70-targeting CAR.

Provided are methods, compositions, uses and articles of manufacture of combination therapies involving immunotherapies, such as adoptive cell therapy, e.g., T cell therapy, and the use of (S)-3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-di-hydro-isoindol-2-yl]-piperidine-2,6-dione, or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, for treating subjects with disease and conditions such as certain B cell malignancies, and related methods, compositions, uses and articles of manufacture. The cells generally express recombinant receptors such as chimeric antigen receptors (CARs). In some embodiments, the disease or condition is a non-Hodgkin lymphoma (NHL), such as relapsed or refractory NHL or specific NHL subtype.