Immunotherapy can induce regressions of even advanced stage cancers, and many of these patients can have prolonged disease remissions.
Joshua Brody, MD
Icahn School of Medicine
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 and BCG), which push the gas pedal of the immune system; checkpoint blockade antibodies (eg, anti-CTLA-4, anti-PD1), 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.
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.
Recently, we developed a novel approach using the patient’s immune system to recognize and “reject” his or her own lymphoma tumors. This “in situ vaccine” approach consists of low-dose radiotherapy to one tumor site and injection of an immune cell stimulant (a TLR agonist) directly into the same tumor site to activate the small number of immune cells (eg, DCs) there. At the vaccine site, DCs instruct and prime antitumor T cells, which then travel throughout the body to eliminate their tumor targets. We treated 60 patients with the in situ vaccine in trials for low-grade B-cell and T-cell lymphoma and it induced partial and complete remissions, some lasting for years. It was equally exciting that—as expected with vaccines—this therapy actually became more powerful with repeated use.
This stark contrast to the paradigm of chemotherapy is encouraging; still, the approach needs to be made even more effective. One likely limitation is that there are very few “professional” antigen-presenting cells, such as DCs, at the tumor site constraining the ability to prime the antitumor T-cell response. Bringing more DCs to the tumor might yield more effective antitumor T cells and a greater number of clinical responses.
Just as red blood cells have erythropoietin and neutrophils have G-CSF, DCs have a predominant growth/differentiation factor known as Flt3L. A recombinant form of the protein recently completed phase I testing in healthy volunteers and was shown to drastically increase the number of DCs in peripheral blood. Preclinical studies in our lab have shown that by injecting this growth factor directly into tumors,the number of intratumoral DCs can be significantly increased (Figure). Hence the “low-hanging fruit” and rationale behind a newly initiated trial for the in situ vaccine at Mount Sinai School of Medicine.
The study [NCT01976585] will enroll 30 patients with low-grade B cell lymphoma in two cohorts to assess for the recruitment of DCs to the tumor site, the induction of antitumor T cells, and the proportion of patients with systemic clinical responses (ie, occurring outside of the radiotherapy field). The study Principal Investigator, Joshua Brody, MD, is working together with clinical collaborator Janice Gabrilove, MD, and scientific collaborators Nina Bhardwaj, MD, PhD, and Miriam Merad, MD, PhD, as well as the Mount Sinai Human Immune Monitoring Center.
The debate over whether the immune system can treat cancer is done. Over the next decade, questions on how best to modulate the immune system to recognize tumors, which tumor antigens are most effectively targeted, and the role of checkpoint blockade, immune stimulants, vaccines, and combinations thereof will predominate as we progress from cancer treatments to cancer cures. For these questions, only enrollment of patients onto clinical trials will provide the answers. The answers, in turn, should provide long and gratifying lives for our patients.
(1) Intratumoral injections of Flt3L to recruit DC to the tumor site.
(2) Low-dose radiotherapy (4 Gy) to the tumor to release tumor-associated antigens.
(3) Intratumoral injections of the TLR agonist poly-IC to activate the tumor-antigen loaded DC.