Product Approvability Recommendations From FDA Advisory Committees:: Inconsistently Sought, Indirectly Obtained.

BACKGROUND: Divisions within the Food and Drug Administration (FDA) often convene meetings of advisory committees, also known as AdComm or Panel meetings. The purpose of many AdComm meetings is for the FDA to obtain outside advice and recommendations on whether to approve a new drug or medical device. Laws and regulations indicate that such Panels are to provide recommendations regarding the approvability of the drug or device by FDA. METHODS: We examine recent AdComm meetings, including a systematic review of drugs and biologics AdComms between 2011 and 2016, to find whether FDA is obtaining Panel recommendations on drug and device approvability in accordance with these laws and regulations. (This article does not contain any studies with human or animal subjects performed by any of the authors.). RESULTS: We find that Panel recommendations on approvability are often not obtained. We further find that, in most cases where Panel recommendations are obtained, voting procedures are such that those recommendations address product approvability in only an indirect manner. CONCLUSIONS: While FDA rightly has the authority to exercise discretion in many aspects of the product approval process, we believe that it must obtain clear recommendations whenever it convenes a Panel to address product approvability.

Immunotherapy of cancer by antisense inhibition of Ii protein, an immunoregulator of antigen selection by MHC class II molecules.

Ii protein suppression is a promising antisense drug-based therapy that dramatically enhances the immunogenicity of tumor cell major histocompatibility complex class II-presented antigenic epitopes. The strength of this approach is that the antisense only needs to be transiently effective in a fraction of the tumor cells. The systemic antitumor immune response generated subsequently eradicates both directly treated cells and distant tumor deposits. The drugs and mechanisms of this therapy are considered, in addition to practical developmental questions.

Turning tumor cells in situ into T-helper cell-stimulating, MHC class II tumor epitope-presenters: immuno-curing and immuno-consolidation.

Immunological control or cure of tumors depends on initiating a robust T helper cell response to MHC class II epitopes of tumor-associated antigens. T helper cells regulate the potency of cytotoxic T lymphocyte and antibody responses. We have developed a novel approach to stimulate T helper cells by converting tumor cells into MHC class II molecule-positive, antigen presenting cells. Furthermore, using antisense methods, we suppress expression of the Ii protein, that normally blocks the antigenic peptide binding site of MHC class II molecules during synthesis in the endoplasmic reticulum. In such gene-engineered tumor cells, the MHC class II molecules pick up antigenic peptides, which have been transported into the endoplasmic reticulum for binding to MHC class I molecules. All nucleated cells create such "surveys of self" to detect viral or malignant transformation. Our method extends that survey of self to MHC class II endogenous tumor-associated antigens. Simultaneous presentation of tumor antigens by both MHC class I and II generates a robust and long-lasting antitumor immune response. Injecting murine tumors with genes, which induce MHC class II molecules and suppress Ii protein, cures a significant number of animals with renal and prostate tumors. We have developed analogous human gene vectors that are suitable for most patients and cancers, because they are monomorphic and active in all HLA-DR alleles. We review our findings, and analyze remaining issues for preclinical study and the design of clinical trials.

Ii-Key/HER-2/neu MHC class-II antigenic epitope vaccine peptide for breast cancer.

PURPOSE: Cytotoxic T lymphocytes (CTL)- and T-helper cell-specific, and major histocompatibility complex (MHC) class-I and class-II peptides, respectively, of the HER-2/ neu protein, induce immune responses in patients. A major challenge in developing cancer peptide vaccines is breaking tolerance to tumor-associated antigens which are functionally self-proteins. An adequate CD4+ T-helper response is required for effective and lasting responses. METHODS: Stimulating anti-cancer CD4+ T cell responses by MHC class-II epitope peptides has been limited by their weak potency, at least compared with tight-binding MHC class-I epitope peptides. Previously, a potent T-cell response to a MHC class-II epitope was engineered by coupling the N-terminus of the pigeon cytochrome C [PGCC(95-104)] MHC class-II epitope to the C-terminus of an immunoregulatory segment of the Ii protein (hIi77-81, the Ii-Key peptide) through a polymethylene spacer. RESULTS: In vitro presentation of the MHC class-II epitope to a T hybridoma was enhanced greatly (>250 times). Now, an Ii-Key/HER-2/neu (777-789) MHC class-II epitope hybrid peptide stimulated lymphocytes from both a healthy donor and a patient with metastatic breast carcinoma. The in vitro primary stimulation with the hybrid peptide strongly activated IFN-gamma release, whereas the epitope-only peptide was weakly active. In fact, the hybrid stimulated IFN-gamma release as well as the wild-type peptide when augmented with IL-12; however, the hybrid was comparable to free peptide in stimulating IL-4 release. This pattern is consistent with preferential activation along a non-tolerogenic Th1 pathway. CONCLUSION: Such Ii-Key/MHC class-II epitope hybrid peptides have both diagnostic and therapeutic applications.

Ii-Key/MHC class II epitope hybrid peptide vaccines for HIV.

The Ii-Key/MHC class II epitope hybrid acts on MHC class II molecules to facilitate replacement of antigenic peptides with the epitope tethered to the Ii-Key motif. Hybrid peptides linking an immunoregulatory segment of the Ii protein (Ii-Key peptide) through a polymethylene bridge to MHC class II epitopes of HIV gp160 or gag are potent vaccines to elicit CD4(+) T cell responses. More potent responses to two MHC class II epitopes, HIV gp160(843-852) or HIV gag(279-292), occurred in mice immunized with Ii-Key hybrid peptides than with epitope-only peptides, as measured in IL-4 and IFN-gamma ELISPOT assays of splenic lymphocytes stimulated in vitro by epitope-only peptides. Both the number of responding cells and cytokine output per cell were increased. The Ii-Key/MHC class II epitope hybrid acts on MHC class II molecules to facilitate replacement of antigenic peptides with the epitope tethered to the Ii-Key motif. Such antigenic peptide constructs create opportunities to enhance greatly Th1 or Th2 responses to MHC class II epitopes for therapeutic purposes.

Tumor immunotherapy by converting tumor cells to MHC class II-positive, Ii protein-negative phenotype.

A potent antitumor CD4(+) T-helper cell immune response is created by inducing tumor cells in vivo to a MHC class II(+)/Ii(- )phenotype. MHC class II and Ii molecules were induced in tumor cells in situ following tumor injection of a plasmid containing the gene for the MHC class II transactivator (CIITA). Ii protein was suppressed by the antisense effect of an Ii-reverse gene construct (Ii-RGC) in the same or another co-injected plasmid. The MHC class II(+)/Ii(- )phenotype of the tumor cells was confirmed by FACS analysis of cells transfected in vitro and by immunostaining of tumor nodules transfected by injections in vivo. Subcutaneous Renca tumors in BALB/c mice were treated by intratumoral injection with CIITA and Ii-RGC, in combination with a subtherapeutic dose of IL-2, to up-regulate the activation of T cells. Significant tumor shrinkage and decrease in rates of progression of established Renca tumors were seen in the groups injected with Ii-RGC, compared with groups in which only IL-2 plus empty plasmid controls were injected. Our method provides an effective immunotherapy warranting further development for human cancers.