Technology

CLL cells with del(17p) typically have loss of functional p53, rendering them refractory to chemotherapeutic agents. However, del(17p) CLL cells activated by CD40 ligand (CD154) are induced to express pro-apoptotic factors to overcome resistance to the cytotoxic activity of p53-dependent drugs, such as fludarabine. To examine whether a CD154-based therapeutic strategy can be developed in vivo for del(17p) and/or fludarabine-refractory CLL, a phase 1b clinical study evaluating an autologous cellular gene immunotherapy is being conducted.

Chronic lymphocytic leukemia (CLL) patients with del(17p) typically have loss of functional P53, rendering them refractory to chemotherapeutic agents. However, del(17p) CLL cells activated by CD40L (CD154) are induced to express pro-apoptotic factors that resensitize cells to the cytotoxic activity of P53-dependent drugs, such as fludarabine (F-ara-A).

Ad-ISF35 is a replication-defective adenovirus (Ad) vector that encodes ISF35, which is a potent immunostimulatory CD40 binding protein designed to maximize stable, high-level cell-surface expression of this molecule.

Signaling via CD40 activates antigen-presenting cells both in vitro and in vivo. CD40 ligation of resting B cells increases antigen-presenting function and induces proliferation and immunoglobulin class switching. Many tumor cells express CD40, including almost 100% of B-cell malignancies and up to 70% of solid tumors. More over, signaling mediated by CD40 / CD154 stimulation can induce cell death in cancer cells making this pathway an attractive target for cancer immunotherapy.

Ad-ISF35 is a replication-defective adenovirus (Ad) vector encoding a membrane-stable chimeric CD154 (ISF35) that can induce expression of costimulatory and death receptor molecules in chronic lymphocytic leukemia (CLL) cells in vitro and in vivo.

Chronic lymphocytic leukemia (CLL) cells with del(17p) typically have loss of functional P53, rendering them refractory to chemotherapeutic agents. However, del(17p) CLL cells activated by CD40L (CD154) are induced to express pro-apoptotic factors that re-sensitize cells to the cytotoxic activity of P53-dependent drugs, such as fludarabine (F-ara-A).

Ad-ISF35 is a replication-defective adenovirus (Ad) vector that encodes ISF35, which is a potent immuno-stimulatory CD40 binding protein designed to maximize stable, high-level cell-surface expression of this molecule. ISF35 can induce expression of costimulatory and death receptor molecules on chronic lymphocytic leukemia (CLL) cells in vitro and in vivo.

Transduction of chronic lymphocytic leukemia (CLL) cells with a replication-defective adenovirus (Ad) encoding recombinant CD154 (Ad-ISF35) induces expression of death receptors and Bid via a P53-independent pathway involving induction of P73. Induction of P73 significantly enhances the sensitivity of P53-defective CLL cells to "P53-dependent" drugs, such as Fludarabine (F-ara-A). Patients with P53-defective CLL who received iv infusions of autologous Ad-ISF35-transduced CLL cells were observed to achieve complete remissions (CR) with subsequent treatment using F-ara-A based treatment regimens,

Transduction of chronic lymphocytic leukemia (CLL) cells with replication-defective adenovirus (Ad) encoding a genetically engineered, membrane-stablized CD154 (ISF35) converts transduced, and "bystander" non-transduced, CLL cells into proficient antigen presenting cells that can induce immunity against autologous leukemia cells.

Chronic lymphocytic leukemia (CLL) is a malignancy of inept antigen presenting B cells (APC) that possibly re-circulate between the blood, marrow, and secondary lymphoid compartments. Studies indicate that transduction of CLL cells ex vivo with the gene encoding the CD40-ligand (CD154) can convert transduced and non-transduced "bystander" CLL cells into proficient APC capable of eliciting immune responses against leukemia-associated antigens.

Following exposure of chronic lymphocytic leukemia (CLL) cells to autologous CLL cells transduced with a replication-defective adenovirus encoding a recombinant CD40-ligand (Ad-ISF35), the CLL cells were induce to express death receptors (CD95 and DR5) and the BH3-interacting-domain death agonist (Bid) via a P53-independent pathway that involved P73.

Chronic lymphocytic leukemia (CLL) cells that have del(17p) typically have loss of functional P53, rendering these cells refractory to standard chemotherapeutic agents, which require activation of P53 for their cytotoxic activity. However, del(17p) CLL cells co-cultured in vitro with cells transduced to express the CD40L (CD154) activate another member of the P53 family of proteins, namely P73, which, like P53, can induce transcription of death receptors and pro-apoptotic proteins and sensitize cells to the cytotoxic activity of "P53-dependent" drugs, such as Fludarabine (F-ara-A).

Chronic lymphocytic leukemia (CLL) is an ideal disease for therapeutic vaccine strategies. While the leukemia cells are usually stealth-like, avoiding T cell recognition, they can be manipulated to become effective antigen presenting cells (APCs), via ligation of CD40 on their surface. This leads to a cascade of events that enable presentation of leukemia antigens to T cells. CLL B cells can manipulated to express CD154 (CD40-ligand) using a replication-defective adenovirus.

CLL cells can be transduced with adenovirus vector to express CD40-ligand (CD154). Ad-ISF35 is the Ad-vector that encodes a novel molecule capable of ligating CD40 on CLL cells. We conducted a phase I clinical trial to evaluate tolerability, toxicities, and clinical activity of a single infusion of autologous ISF35-transduced CLL cells.

ISF35 is a novel CD40-binding protein designed to maximize stable, high-level surface-expression of this potent immuno-stimulatory molecule on cells transduced to express this protein. In a recent clinical study, patients with chronic lymphocytic leukemia (CLL) received intravenous infusions of autologous leukemia cells transduced ex vivo to express ISF35 using a replication-defective adenovirus vector (Ad-ISF35).

Non-Hodgkin lymphoma (NHL) is a highly prevalent disease with approximately 30,000 cases diagnosed every year in the United States. Despite advance in the treatment of NHL the majority of patients relapsed after chemotherapy treatment and frequently die of disease progression or treatment related complications. Therefore there is a need for novel and effective treatment strategies for the treatment of patients with NHL.

Chronic lymphocytic leukemia (CLL) is an ideal disease for therapeutic vaccine strategies. While the leukemia cells are usually stealth-like, avoiding T cell recognition, they can be manipulated through ligation of CD40 on their surface to become very effective antigen presenting cells (APCs).

Chronic lymphocytic leukemia (CLL) is a malignancy ideally suited for therapeutic vaccines. CLL B cells, readily available from blood, express surface antigens that can be targeted for immune-recognition. Although usually stealth-like, CLL cells can be stimulated through ligation of CD40 by CD154, to express immune co-stimulatory molecules, such as CD80, CD86, and adhesion molecules (e.g. CD54), allowing them to stimulate T cells against leukemia-associated antigens.