Combinations & Methods of Use for Recombinant CD4 T Cell Receptors for Direct Tumor Recognition of Antigen
CD4+ T cells recognize peptide fragments presented on MHC class II (HLA class II in humans). In addition to antigen-presenting cells such as macrophages and dendritic cells, many human cancer cells express MHC class II constitutively or in an IFN-γ-inducible manner although the role of MHC class II expression on human cancer cells is largely unknown.
Tumor antigen-specific CD4+ T helper cells play critical roles in the induction and maintenance of anti-tumor immune responses by providing “CD4-help”. Activation of CD4+ T cells at the local tumor sites is believed to help overcome multiple immunosuppression mechanisms and promote tumor eradication by the immune system. However, because of the frequent lack of functional antigen-presenting cells at the local tumor sites, activation of the CD4+ T cells and therefore the provision of CD4+ T help at the local tumor site is severely limited. There is accordingly, an ongoing and unmet need to provide new compositions and methods such that activation of CD4+ T cells and therefore provisions of CD4+ help can be achieved.
This invention describes sequences of TCR α and β chain genes from a novel tumor-recognizing CD4+ T cell clone as well as a method to prepare a large number of tumor recognizing CD4+ T cells by TCR gene transfer.
Roswell researchers have discovered that there are two distinct types of tumor antigen-specific CD4+ T cells. A part of tumor antigen-specific CD4+ T cells, that we named “tumor-recognizing CD4+ T cells (TR-CD4)”, directly recognizes MHC class II-expressing cancer cells in antigen-specific and MHC class II-restricted manners. In contrast, other part of the same antigen-specific CD4+ T cells, “non-tumor-recognizing CD4+ T cells (NTR-CD4)”, only recognizes the exogenous tumor antigen protein after processing by antigen-presenting cells.
Because of their different abilities in direct recognition of cancer cells, these two types of CD4+ T cells (TR-CD4 and NTR- CD4) are considered to play different roles at the local tumor site, i.e., TR-CD4 efficiently provide CD4-help by direct recognition of cancer cells.
This invention takes advantage of the fact that TR-CD4 cells provide CD4 help by direct recognition of cancer cells by using this function to provide TCR polypeptides and recombinant polynucleotides encoding them for use in novel prophylactic and/or therapeutic treatment modalities and compositions. By engineering T cells to express the TCRs researchers can endow any CD4+ cell with the capability to directly recognize tumor antigen-expressing cancer cells, without requiring presentation of the antigen by an antigen presenting cell. Thus, the present invention includes compositions and methods that are useful for creating and using TR-CD4 cells for improved care of cancer patients.