Larry W. Kwak, M.D., Ph.D., Laboratory
Research in Cancer Immunotherapy
Our laboratory is focused on cancer immunotherapy, developing treatments, such as vaccines, that stimulate the immune system to recognize and attack cancer cells. The immune system protects the body through special cells that patrol the body and recognize and respond to marker substances on cells called antigens. An effective cancer vaccine must stimulate an immune response (by producing antibodies) and direct it at the correct target (the antigen), and be powerful enough to overcome the cancer cells’ own defenses against B cells and killer T cells.
Our laboratory’s central hypothesis is that, in a variety of B cell cancers, there is an the idiotypic component (an idiotype is a protein specific to a patient’s tumor) of the malignant B cells that provides a molecular and antigenic target for T cells, allowing them to be used as the focus for an effective cancer immunotherapy regimen.
As presented at the Plenary Session of the 2009 American Society of Clinical Oncology, an idiotype protein vaccine developed from formulations and testing originally devised by Dr. Kwak, became one of the first therapeutic cancer vaccines to show efficacy in a randomized, controlled clinical trial. Patients with follicular lymphoma treated with this idiotype protein vaccine + GM-CSF, which elicits lymphoma-specific CD8+ T cells and molecular remission, lived disease-free for over a year longer than patients who did not. The vaccine, BiovaxIDTM, was the result of a technology transfer of this “homegrown” therapeutic agent to industry.
Translational development of the first therapeutic lymphoma vaccine
Currently, our laboratory is focused on the development of novel, second generation cancer vaccines. Based on the original hypothesis—that targeting antigens to chemokine (a kind of protein) receptors on antigen-presenting cells induces a strong T-cell immune response—we have shown that genetically fusing tumor and HIV antigens to a proinflammatory chemokine elicits potent anti-tumor immunity in animal tumor models (Science, 2002). We are now refining these chemokine-antigen fusion DNA vaccines for their use as therapies and determining mechanisms by which candidate antigens are cross-presented to T cells.
Candidate chemokine-idiotype (scFv) fusion proteins
Another independent human immunotherapy strategy pioneered in our laboratory involves adoptive transfer of tumor-specific T-cell immunity from a healthy donor who has been vaccinated to a person with cancer. Our hypothesis is that it is easier to break the tolerance to tumor antigens using the cells of immunized healthy donors, rather than those of cancer patients, whose immune system may be compromised from the underlying disease or prior treatment.
In collaboration with the Department of Stem Cell Transplantation, we have successfully applied this strategy to the stem cell transplant setting, transferring the T-cell immunity of a healthy stem cell transplant donor. Prior to transplantation, we immunize the healthy donor, thus eliciting an immune response against a defined tumor antigen.