Joshua Brody, MD
Icahn School of Medicine
at Mount Sinai The Tisch Cancer Institute
Immunotherapy can induce regressions of even advanced stage cancers, and many of these patients can have prolonged disease remissions. Three broad approaches have moved immunotherapy forward: immunostimulants (eg, IL-2
), which push the gas pedal of the immune system; checkpoint blockade antibodies (eg, anti-CTLA-4
), which cut the brake lines; and vaccines (eg, sipuleucel-T
), which can steer the immune system toward recognizing specific antigens. Unfortunately, the metaphor falls short. If cars had as many gas pedals and brake pedals as the immune system, accidents and gridlock would be endless. The system usually runs itself seamlessly; we have tried clumsily to drive it with halting successes and failures, acknowledging that an owner’s manual would be helpful. Basic immunologists have been writing this manual for the past 40 years and although it’s far from complete, immunotherapists have been reading the early drafts and trying to implement the lessons with some remarkable early success.
A recent example of basic science discovery was the 2011 Nobel Prize in Medicine
, which was awarded for the discovery of dendritic cells (DCs) and the molecular switches that turn them on, the Toll-Like Receptors (TLR). Today, the clinical significance of these basic discoveries has an opportunity to be realized with new clinical grade reagents. Flt3L, a DC growth factor, has completed phase I testing and shown to be safe and effective. Meanwhile, several TLR agonists (eg, poly-IC, imiquimod/resiquimod, CpG) have been shown in a multitude of clinical trials to stimulate activation of distinct subsets of DCs. This progress in basic and applied immunology sits atop our decision tree of possible immunotherapeutic combinations, weighing down the branches, and yielding some low-hanging fruit.
Standard Therapy for Lymphoma
Lymphoma is the fifth most common cancer nationally and one of the few still increasing in frequency. The World Health Organization recognizes more than 60 types of lymphoma, and the most prevalent subtypes fall within the group of low-grade B-cell lymphomas. For these diseases, chemotherapy and antibody therapy induces remissions in most patients, but disease generally recurs and chemotherapy becomes less effective with each successive use. A promising new generation of kinase inhibitors similarly has high response rates but limited durations of response. Ultimately, therapy resistance develops and low-grade lymphomas are incurable with standard therapy. Novel therapies that attack the tumor in a completely different way are needed. If cancer vaccines could become more powerfulwith each successive use—just as we see with booster vaccines in infectious disease—we could fundamentally change the paradigm of diminishing responses to therapy.
The first generation of vaccines tested in large trials were known as idiotype vaccines, described preclinically in 1987 and clinically in 1992 by Ronald Levy, MD, and colleagues at Stanford. Although this elegant approach frequently induced antitumor antibody responses, the demonstration of antitumor T-cell responses and clinical responses were rare. Ultimately, two large randomized trials showed no clinical benefit with idiotype vaccines.