Madhav Dhodapkar, MBBS
Traditional chemotherapy remains the most common cancer treatment, but the fast-growing field of immunotherapy is set to change that. The FDA has approved a handful of immunotherapy treatments. Many more are in clinical trials. And scientists continue to uncover exciting new avenues for exploration.
The foundations for these discoveries are being built by researchers like Madhav Dhodapkar, one of the world’s leading experts in cancer immunology and immunotherapy.
While at Yale, Dhodapkar participated in the earliest studies on immune checkpoint inhibitors, which “turn on” tired immune cells. Those studies led to some of the most successful cancer immunotherapy treatments now available — PD-1 inhibitors like Pembrolizumab (Keytruda) and Nivolumab (Opdivo), and CTLA-4 inhibitors like Ipilimumab (Yervoy).
Since those early studies, Dhodapkar has continued to expand our understanding of how the immune system fights early cancer cells and what makes it fail.
Much of his work focuses on myeloma, a common type of blood cancer. Myeloma’s precursor stage is called MGUS, which stands for monoclonal gammopathies of undetermined significance. A person with MGUS has rogue mutated cells that could become cancerous but haven’t yet (and, in a lot of patients, they never do). Dhodapkar wants to know exactly why that is, because the answer could reveal a lot about how the immune system works to prevent cancer — and ways to assist it.
One of Dhodapkar’s biggest findings was the fact that the immune system is already aware of these rogue MGUS cells, even though they may not be visible to pathologists. In an influential study, Dhodapkar and colleagues isolated T-cells (immune cells) from the blood and bone marrow of MGUS patients, then exposed the T-cells in vitro to the patients’ mutated (but still pre-malignant) plasma cells. The T-cells immediately mounted a strong attack against the mutated plasma cells.
This discovery provided some of the earliest evidence that the immune system recognizes irregular cells even before they become cancerous.
Dhodapkar’s lab has also done a lot of work exploring the role that dendritic cells play in the immune system. Dendritic cells are so named because they look a little like a tree, with lots of probing branches. They use that extensive surface area to interface with many surrounding immune cells, making dendritic cells a key regulator of the immune system. One way they do this is “antigen presentation” — exposing the surrounding immune cells to the harmful intruder, in this case a cancerous cell, so the immune cells know to make antibodies.
Dhodapkar pioneered research demonstrating that dendritic cells could both activate and suppress human immunity. He also led the first studies showing that it’s possible to directly target dendritic cells in humans to elicit an immune response. His team is exploring one potential cell therapy of modifying a patient’s dendritic cells with an “antigen payload,” spurring a strong anti-cancer reaction from the immune system. Approaches like these could lead to a new generation of immunotherapy vaccines.
Throughout their broader investigation of cancer immunology, Dhodapkar’s lab also discovered a whole new type of immune cell, dubbed type II NKT-TFH. While the typical NKT cell (natural killer t-cell) is usually a key ally in the fight against cancer, the type II NKT-TFH cell appears to have directly opposing properties. Stimulated by inflammation and volatile fatty cells, type II NKT-TFH cells can actually spur cancer’s growth. Dhodapkar describes the relationship between typical NKT and type II NKT cells as yin and yang. What’s not yet clear is what purpose this balance typically serves – a prime area for future study.
Immunotherapy is still a young field. Many questions remain to be answered. To make faster progress toward effective treatments, researchers like Dhodapkar and his team are exploring many avenues at once, unearthing knowledge that will drive discoveries for decades to come.
- Targeting human dendritic cells in situ
- Manipulating human NKT cells via dendritic cells
- Immune response to stemness genes and immunologically targeting cancer stem cells
- Lipid-reactive immune cells (type II NKT)
- Risk factors for multiple myeloma
- Progression of precursor lesions to cancer
- Mouse models for studying myeloma in humans
Straight from the Scholar
“Emory is home to a major comprehensive cancer center with a large clinical footprint. Our goal is to develop an infrastructure for cancer immunotherapy here that involves multiple disciplines and facilitates testing novel first-in-human immune therapies. Part of the attraction to move was because of the investment from GRA and the Winship Cancer Institute into immunological approaches to treat or prevent cancer.”