Today’s sessions at the inaugural International Cancer Immunotherapy Conference focused on four main areas: viruses and cancer; biomarkers; imaging immune responses; and the microbiome. I won’t be able to report on all 16 talks, but I will try to touch on the highlights.
Viruses and Cancer
Cornelis (Kees) Melief, M.D., Ph.D., of Leiden University Medical Center, The Netherlands, opened this session with a helpful reminder: “the cause of cancer dictates the nature of immunogenicity.” What he meant was that different cancers are more or less recognizable by the immune system depending on how the cancer cells acquired their transformed phenotype in the first place. Some of the most effective immunotherapies work against virus-caused cancers. That’s because viral antigens are clearly distinguishable from human proteins and the immune system has an easier time finding these invaders. In two cases of common virus-caused cancers—liver cancer and cervical cancers—there are very effective preventive cancer vaccines available; by vaccinating against the virus—hepatitis B virus (HBV) or human papillomavirus (HPV), respectively—you effectively prevent the development of cancer.
But the immunogenicity of virally caused cancers also makes them good targets for therapeutic immunotherapies—ones designed to treat rather than prevent the cancer. On this front, Sjoerd van der Burg, Ph.D., also of Leiden University, presented work on a vaccine made from long peptides derived from HPV. Van der Burg had shown previously that such a vaccine can effectively treat early-stage cervical cancer. However, in patients with late-stage disease, the vaccine is not typically effective. That’s because, as van der Burg showed, the immune system of these patients is much more heavily suppressed and the vaccine can no longer stimulate it adequately to fight the raging cancer. The main suppressive culprit is a population of immune cells called myeloid-derived suppressor cells (MDSC) that hold immune responses in check in the local environment of the tumor. These cells normally play a protective role, preventing excess inflammation and autoimmunity (a theme of the conference; see yesterday’s blog post), but they can also be a major liability in the context of cancer. It seems that in many cases, well-developed tumors have found a way to coopt the suppressive powers of these cells to their own benefit.
Interestingly, van der Burg and others have found that some types of chemotherapy can preferentially knock out the MDSCs in the tumor environment, allowing the HPV vaccine to trigger a more powerful immune response. For that reason, a clinical trial was started testing the concurrent administration of the vaccine along with chemo for patients with advanced cervical cancer.
Another virus that can cause cancer is Epstein-Barr virus (EBV). Many people are infected with this virus, but most of us can keep it safely under control. Sometimes, however, the virus can escape immune surveillance and do damage. One situation where this is much more likely to occur is after a stem cell transplant—a common procedure for certain types of blood cancer. In this context, the virus can become active and cause lymphoma, a cancer of B cells. Helen Heslop, M.D., of Baylor College of Medicine, has succeeded in greatly reducing the likelihood of this happening by giving the patient virus-specific T cells from a matched donor. These T cells are able to restore EBV immunity in a very high percentage of cases. Heslop has also developed an off-the-shelf version of the virus-specific T cells, and has recently begun experimenting with combining virus-specific T cells with CAR technology to deal with persistence problems that sometimes affect CAR T cells (see yesterday’s discussion).
Perhaps the most provocative talk of the session came from Rafi Ahmed, Ph.D., of Emory University, who presented work from his lab that casts doubt on the common understanding of how checkpoint antibodies work. Using a model of chronic infection in mice, Ahmed has found that PD-1 checkpoint antibodies that are supposedly “non-depleting” (see discussion from Day 1), may actually deplete T cells in certain organs, by triggering engulfment by macrophages. This is potentially a big problem, since in most cases you want the T cells to stick around and fight the cancer. The exact relevance of the finding to humans was not clear, however, since humanized antibodies don’t interact with macrophages in quite the same way as in mice. Nevertheless, Ahmed’s finding reinforces the notion that you can’t ignore the back end of the antibody when designing these drugs.
Responders and Non-responders
Kicking off the next session, on biomarkers, was Ira Mellman, Ph.D., of Genentech and also CRI’s Scientific Advisory Council, who noted that even with the incredibly promising immunotherapies known as checkpoint inhibitors, only 10%-30% of patients typically respond. A pressing goal for the field, therefore, is identifying which patients are most likely to respond to these agents, and figuring out how to improve treatment options for the non-responders. Mellman focused in on PD-L1 staining in the tumor environment as a potentially predictive biomarker. Conventional wisdom in the field is that tumors that express high levels of PD-L1 will tend to respond better to anti-PD-1/anti-PD-L1 treatments. But Mellman pointed out that for many tumors, PD-L1 staining on tumor cells is actually less predictive than staining on immune cells in the tumor. This result is a bit perplexing given the commonly accepted view that PD-1/PD-L1 checkpoint inhibitors work by blocking cancer cells from stepping on the PD-1 brake on T cells.
Taking this clinical finding back to the lab, Mellman used it as a jumping off point to investigate mechanistically how PD-1 signaling works. Using a re-constituted model of PD-1 proteins in a cell membrane, he found evidence that PD-1 signals act predominantly on co-stimulatory molecules like CD28 rather than on the T cell receptor. This could help explain why PD-L1 staining on immune cells better predicts responses to anti-PD-1 therapy in some types of cancer. These immune cells, which include myeloid derived suppressor cells, may be giving a negative co-stimulatory signal to T cells, holding them in check. PD-1 checkpoint inhibitors interrupt this negative signal, allowing T cells to become activated.
Continuing the theme of responders and non-responders, Pam Sharma, M.D., Ph.D., of MD Anderson Cancer Center, who is also a CRI/SU2C Dream Team grantee, presented work that she has done looking at tumor samples obtained from patients undergoing surgery to understand mechanistically why some patients fail to respond. It was through such work on bladder cancer tissues that she and others were able to identify a role for a signaling pathway called ICOS in predicting good responses to treatment with the checkpoint inhibitor ipilimumab (anti-CTLA-4). Bladder cancer patients treated with ipilimumab who responded well tended to have higher levels of ICOS activation, raising the possibility that activating this pathway in non-responders may be a way to improve responsiveness to therapy.
Based on the number of mutations found within them, some types of tumors are naturally more prone to immune recognition than others. Melanoma is one such “hot” tumor, with many mutations. On the “colder” end of the spectrum is prostate cancer, which has many fewer mutations. Can a cold tumor be converted into a hot tumor? Sharma showed that, indeed, treatment of prostate cancer patients with ipilimumab causes immune cells to traffic into tumors. However, no patients treated this way had a complete response as a result. Again using tissue samples from surgical specimens, Sharma was able to pinpoint the reason why: the tumors up-regulated other inhibitory immune pathways. This result raises the possibility that combination immune checkpoint blockade might benefit patients with prostate cancer.
During a working lunch session, we were treated to visually stimulating presentations from Alex Huang, M.D., Ph.D., of Case Western Reserve, a former CRI post-doc, and Ron Germain, M.D., Ph.D., of the National Institute of Allergy and Infectious Disease. Both investigators wowed the audience with precise 2D and 3D visualizations of lymph node architecture, which one conference goer compared to “art.”
And Carl Figdor, Ph.D., from Nijmegen Centre for Molecular Life Sciences, The Netherlands, presented very interesting work he has done to create synthetic immune actors, including “nanoparticles” loaded with immune regulating chemicals and flexible scaffolds that function like synthetic dendritic cells that Figdor calls “nanoworms.”
Your Inner Microbes
Following the lunch session (thankfully not during), the topic shifted to the interactions between the microbes living in our gut and our immune system. As Laurence Zitvogel, M.D., Ph.D., of Gustave Roussy Cancer Center in France, pointed out, humans contain within them more bacterial cells than human cells—by an order of about 10:1. What this means, in effect, is that we are supraorganisms, colonies within ourselves. Immunologists have known for a long time that the microbes living on and in us shape the development of our immune system. What has become clear in recent years is that these microbial hitchhikers also influence the way we respond to cancer treatments. Many cancer treatments, such as chemotherapy and immunotherapy, can disrupt the delicate balance of microbes in our gut, and even the integrity of our intestinal lining. When that happens, things can get messy—immunologically speaking.
Zitvogel wanted to know: can the bacterial composition of our guts be altered in such a way that the efficacy of checkpoint blockade immunotherapy is maintained but the toxicity is limited? In her talk, she presented tantalizing findings that suggest that, indeed, bacterial species can affect both aspects of checkpoint blockade therapy.
Finally, the last talk of the day was given by current CRI postdoctoral fellow Jason Hudak, Ph.D., of Harvard Medical School, who presented his work on a clever technique he has developed for labeling different components of bacteria with different colored fluorescence. Called “click chemistry,” the technique involves feeding the bacteria a synthetic compound that mimics a natural nutrient but has an extra bit of chemical wizardry that allows fluorescent chromophores to be attached. The multi-colored bugs can then be followed as they interact with immune cells, and their distinctly labeled chemicals allow for easy tracking under the microscope. The technique promises to greatly enhance our understanding of how bacteria—and the chemicals they make—can lead to inflammation and colorectal cancer.
There was a concurrent session today, on companion diagnostics and assay harmonization, that I couldn’t attend, but I will present highlights from that session in a future blog.
Check back tomorrow for the highlights from the last day of the inaugural International Cancer Immunotherapy Conference.