Novel anti-glioblastoma therapeutic vaccines based on optimal activation of tumor-specific CD4+ T helper cells
ProgettoABSTRACT
Background
Although relevant progress has been made in immunotherapy of cancer by the use of immune checkpoint
inhibitors and in part therapeutic vaccines, unfortunately both approaches work poorly for glioblastoma
(GBM), the most malignant tumor of central nervous system. In particular, vaccination strategies using MHC
class I-bound tumor-specific peptides have encountered critical difficulties due to the limited effect of these
vaccines in stimulating and maintaining MHC class-I restricted tumor specific CD8+ effector cells (CTL).
Hypothesis
Our working hypothesis prioritizes instead the triggering of tumor-specific MHC class II (MHC-II)-restricted
CD4+ T helper (TH) cells, as these cells, hierarchically, are fundamental to both initiate all adaptive immune
responses and maintain the proliferation and cytolytic activity of CTL, the terminal effectors of anti-tumor
immunity. Thus, in our view, without a strong and persistent activation of tumor specific TH cells, the success
of immunotherapeutic vaccination approaches for cancer will be limited.
Aims
Our working hypothesis, based on previous solid experimental results, will be to render tumor cells MHC-IIpositive
and then surrogate presenting cells (APC) for their own tumor antigens to TH cells. This will be
attempted by transferring the MHC-II transactivator (CIITA) discovered in our laboratory, into glioblastoma
cells. Our major aim is to construct an operating framework that will lead us to apply the resulting knowledge
to clinical setting for a better approach of therapeutic vaccination and treatment of glioblastoma
Background
Although relevant progress has been made in immunotherapy of cancer by the use of immune checkpoint
inhibitors and in part therapeutic vaccines, unfortunately both approaches work poorly for glioblastoma
(GBM), the most malignant tumor of central nervous system. In particular, vaccination strategies using MHC
class I-bound tumor-specific peptides have encountered critical difficulties due to the limited effect of these
vaccines in stimulating and maintaining MHC class-I restricted tumor specific CD8+ effector cells (CTL).
Hypothesis
Our working hypothesis prioritizes instead the triggering of tumor-specific MHC class II (MHC-II)-restricted
CD4+ T helper (TH) cells, as these cells, hierarchically, are fundamental to both initiate all adaptive immune
responses and maintain the proliferation and cytolytic activity of CTL, the terminal effectors of anti-tumor
immunity. Thus, in our view, without a strong and persistent activation of tumor specific TH cells, the success
of immunotherapeutic vaccination approaches for cancer will be limited.
Aims
Our working hypothesis, based on previous solid experimental results, will be to render tumor cells MHC-IIpositive
and then surrogate presenting cells (APC) for their own tumor antigens to TH cells. This will be
attempted by transferring the MHC-II transactivator (CIITA) discovered in our laboratory, into glioblastoma
cells. Our major aim is to construct an operating framework that will lead us to apply the resulting knowledge
to clinical setting for a better approach of therapeutic vaccination and treatment of glioblastoma