The clinical application of immunotherapy for cancer is rapidly moving forward in multiple areas, which incorporate the adoptive transfer of antitumor-reactive T cells and the use of 'therapeutic' vaccines. Both clinical and immunologic endpoints have shown new promise to the field. Novel dendritic cell-based vaccine strategies designed in the laboratory and proven in preclinical animal tumor models are now entering the clinic, with the intent of providing therapeutic efficacy. Improvements on this approach involve breaking tolerance to tumor 'self' antigens by inhibiting regulatory cells, boosting T cell co-stimulation, and administering combinations of recombinant cytokines and other defined molecules with 'immuno-enhancing' activities. Development of these improvements is the primary research interest of Dr. Mule.
On the basis of encouraging data from their preclinical studies, Dr. Mule and his colleagues initiated and completed two phase I clinical trials of autologous tumor lysate/keyhole limpet haemocyanin (KLH)-pulsed dendritic cells (TP-DCs) in children and adults with advanced solid tumors. The DCs, characterized as immature by phenotypic marker profiling, yielded both immunologic and very modest clinical responses. Immunologic assays revealed evidence of the induction of peripheral blood T-cell reactivity to both KLH and tumor lysates after immunization, particularly in children.
Because durable and complete regression of established tumors has been difficult to achieve through administration of TP-DCs alone, Dr. Mule and his colleagues have embarked on a new series of clinical trails to evaluate potential improvements in their DC-based vaccine strategy that incorporate intratumoral delivery of KLH-pulsed DCs; systemic administration of interleukin-2 (IL-2); use of locally produced secondary lymphoid tissue chemokine; and the setting of lymphopenia-induced, homeostatic-driven T-cell proliferation. These clinical trials include (1) a phase Ib trial assessing autologous TP-DCs as a tumor vaccine administered with or without IL-2 in patients with metastatic melanoma; (2) a phase II trial assessing autologous TP-DCs as a tumor vaccine administered with low-dose IL-2 in patients with colorectal cancer; (3) a phase I trial assessing intratumoral administration of autologous DCs activated by granulocyte-macrophage colony-stimulating factor and interleukin-4 as a vaccine in muscle-invasive bladder cancer; (4) a phase I trial of escalating doses of fludarabine followed by intranodal delivery of MHC class I/II peptide-pulsed DCs in patients with chemotherapy-naive metastatic melanoma; (5) a randomized phase II trial of fludarabine followed by intranodal delivery of peptide-pulsed DCs with or without autologous lymphocyte infusion; (6) a phase II trial of TP-DC vaccines early after autologous hematopoietic stem cell transplantation to prolong progression-free survival in children with sarcoma; and (7) a phase I clinical study assessing autologous DCs gene-modified to secrete secondary lymphoid tissue chemokine as a vaccine to enhance T-cell priming in patients with advanced solid tumors.