Chronic lymphocytic leukemia (CLL) is the most common adult leukemia and is still considered incurable, mandating development of improved treatment strategies. While most CLL patients respond to initial chemotherapy, approximately 10-20% of newly diagnosed patients and more than 50% of relapsed patients have limited or no response to cytotoxic agents.
These chemotherapy resistant patients frequently have CLL cells that have high-risk cytogenetic abnormalities, such as deletions in the short arm of chromosome 17 (17p-) and/or dysfunctional TP53. Patients with 17p- and/or dysfunctional TP53 respond poorly to chemoimmunotherapy and have a short median survival relative to that of patients with functional TP53. As such, the therapeutic options for patients with 17p- and/or dysfunctional TP53 are limited and usually involve high-risk treatments or allogeneic stem cell transplant, which has a high risk of mortality.
Our proposal provides a potential solution to this problem. We discovered that adenovirus vector transduction of CLL cells with ISF35 (a recombinant CD154) could enhance in vitro and in vivo the sensitivity of leukemia cells to drugs such as fludarabine in a TP53-independent manner (Dicker F. et al, Blood 2006. Castro JE. et al; ASH-2009 meeting abstract). This results from activation of another member of the TP53 family, namely P73. We found CD40 ligation activates P73 in both transduced and bystander leukemia cells and induces the CLL cells to become efficient antigen presenting cells that are capable of inducing host anti-leukemia immune responses. Activation of this alternative pathway can circumvent the resistance of TP53-deficient CLL cells to anticancer drug therapy.
As such, cell-gene immune therapy provides for a novel strategy to re-sensitize resistant TP53-deficient leukemia cells. Patients will receive 3 infusions of autologous CLL cells transduced with ISF35 followed by only 3 cycles of chemoimmunotherapy with FCR (fludarabine, cyclophosphamide and rituximab).
In preliminary work we have found that infusion of Ad-ISF35 transduced autologous leukemia cells causes systemic activation of bystander leukemia cells, rendering the entire leukemia-cell population sensitive to anti-cancer treatments.
To date, two patients with refractory TP53-deficient leukemia have completed therapy on this protocol and have achieved a complete remission. Alliance for Cancer Gene Therapy funds will be used to continue this important work and to perform correlative science studies and clinical monitoring of patients who will enroll in this clinical study. The results generated in this proposal may allow for eventual approval for such gene therapy and offer new hope for patients with intractable leukemia.
This Alliance for Cancer Gene Therapy Research Fellow is funded in part by Swim Across America.
