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How the immune system can be harnessed to kill cancer

Understanding and improving on immunotherapies was a major focus at the 2014 AACR Annual Meeting. New studies are clarifying the reasons that immunotherapies have failed in some cancer types, and are revealing ways that the powerful potential of immunotherapies can be harnessed to improve the treatment of all cancer patients.

June 5, 2014 — The sheer number of sessions dedicated to understanding the role our immune systems play in cancer development and progression at the 2014 Annual Meeting of the American Association for Cancer Research (AACR) made it abundantly clear that cancer researchers believe this to be an extremely valid and promising avenue of research. While immunotherapy—a treatment that uses the immune system to halt cancer progression—has yet to show significant benefits in prostate cancer patients, numerous advances are clarifying the underlying reasons. Every day scientists are uncovering promising strategies to train and unleash an army of immune cells against many different tumor types. Here we highlight several of this year’s AACR tumor immunology and immunotherapy talks.

Tumor cells can die in many ways; some ways alert the immune system and can be taken advantage of therapeutically

Dr. Laurence Zitvogel: “Immunogenicity of cell death: A new paradigm for cancer cure”

“There is no cure in the absence of a productive anti-tumor immune response,” pointed out Dr. Laurence Zitvogel, of the Institut Gustave-Roussy in France, referring to studies showing that radiation therapy and chemotherapies fail to have an effect without immune system engagement. Critical to immune activity against tumors are T-cells, a specialized type of immune cells that recognize and kill “foreign” or “dangerous” cells, including tumor cells. The ability of T-cells to kill tumor cells requires a cascade of events. Tumor cells first need to die an “immunogenic” cell death, meaning that dying cells release molecules (such as HMGB1) that alert and turn on the immune system, revving it up from zero, to instant-go. In model studies of breast cancer, Zitvogel found that HMGB1 was essential for the effects of oxaliplatin chemotherapy. After immune cells are stimulated by HMGB1, they release proteins called “interferons,” that prompt other immune cells in the cascade to activate. One effect of interferons is to stimulate cells to produce IP-10, a molecule that attracts T-cells into the tumor. The final result of this process is the production of an army of anti-tumor T-cells that then do recon inside the body, scouting out any other tumor cells to target with T-cell sniper fire. However as tumors progress, the expression of HMGB1 can be zeroed out– a means for tumors to escape from T-cell surveillance.

Dr. Zitvogel discussed the clinical applications of these findings, including measuring immune activity to predict patient outcome. Having greater numbers of tumor-killing T-cells and/or larger ratios of tumor-killing versus tumor-promoting immune cell types within tumors, has been associated with better outcomes in several cancer types. Zitvogel pointed out that HMGB1 and other signature immune-activation molecules are possible biomarkers for predicting therapeutic responses and patient outcomes. In a Phase III clinical trial of combination chemotherapy (taxane plus anthracyclin), the level of MX1, a gene that is highly activated by interferons, predicted interferon levels and better patient responses to chemotherapy. In another clinical trial, the initial levels of MX1, and another interferon-regulated gene (IRF1), predicted breast cancer patient responses to neoadjuvant chemotherapy. (Neoadjuvant therapy is a treatment given prior to any surgery or radiation.) These studies indicate that the immunogenic molecules released from dying tumor cells and awaken the immune system, are important for the therapeutic effects of chemotherapy, and these molecules may serve as drug targets and predictive biomarkers.

Immunoediting vs. Immunosuppression: How do tumors evade the immune system?

Dr. Robert Schreiber: “Cancer immunoediting: applying mechanistic insights to cancer immunotherapy”

It is thought that a completely healthy and fully equipped immune system is capable of recognizing and killing-off growing tumors. But tumors can learn wicked tricks to escape immune “surveillance.” “Immunoediting” is one of those tricks—a mechanism, in which the tumor evolves to lose expression of the proteins that alert the immune system of imminent danger. Then T-cells, the major immune cell type that kills tumor cells, can no longer “see” and hence kill, tumor cells. Another trick that tumors use to escape from the immune system is “immunosuppression,” in which tumors equip themselves with ways to turn off T-cells that would otherwise recognize and kill the tumor cells. (Stay tuned for more on the discovery of a new immunosuppression mechanism, by Dr. Fearon, whose AACR talk is described below.)

Dr. Robert Schreiber, of the Washington University School of Medicine, MO, discussed evidence that both immunoediting and immunosuppression can occur together, making it that much harder for a body to rid itself of cancer cells.

A T-Cell primer: T-cells target and kill dangerous cells that express unfamiliar antigens, or proteins. How this works, is that every T-cell born expresses a unique T-cell receptor (TCR) that is generated by programmed steps of genomic mutations in the TCR gene. The TCR is the molecule that the T-cell uses to detect its victims: the TCR and target are rather like tragically star-crossed soul-mates—fated to come together, yet doomed in the end (at least the target usually is). When the TCR finds a target, the T-cell becomes activated and divides over and over, generating an army of killer T-cell clones. To avoid autoimmunity, where T-cells run around attacking normal cells in the body, T-cells are first raised in a special T-cell nursery where almost all native “self” antigens are expressed by the supporting cells, and any T-cell with a TCR that recognizes self-antigens commits suicide. The T-cells that survive this selection process should only detect previously unencountered antigens—that is, those from foreign/non-self species, or self-proteins that are mutated such as in cancer, or self-proteins that are only expressed under conditions of stress and not in the T-cell nursery.

In a series of studies in mice, Schreiber and colleagues first demonstrated that anti-tumor T-cell responses (via the TCR) are mounted against certain mutated proteins expressed by tumor cells. But due to immunoediting — weeding-out of detectable tumor cells by T-cells — either only tumor cells without such mutated proteins survive, or tumor cells survive by turning off expression of the mutant genes.

Schreiber went on to show, that even after immunoediting by T-cells, immune responses against tumors can still occur if checkpoint inhibitor therapies (Yervoy (ipilimumab) and Nivolumab) are given, which release T-cells from a tumor- induced lethargy. This indicates that in addition to evading T-cells via immunoediting, tumors are doing other things to suppress the immune system. In addition, he found that Yervoy and Nivolumab released T-cells from immunosuppression through different means. Yervoy treatment caused killer T-cells to proliferate, while Nivolumab caused changes in T-cell metabolism. Treatment with both Yervoy and Nivolumab resulted in both changes, plus the generation of super-activated killer T-cells.

How some tumors inhibit anti-tumor immune responses– and ways to get around it

Dr. Douglas Fearon: “The Dominant Immune Suppressive Process in a Model of Pancreatic Ductal Adenocarcinoma: A Therapeutic Target”

A class of immunotherapy drugs termed “checkpoint inhibitors” work by waking up immune cells from a tumor-induced slumber and activating them to get back into the tumor-killing business. Clinical trials with checkpoint inhibitor drugs including Yervoy and Nivolumab, have been very successful in certain patients with melanoma and some other cancers, and can induce long-term, complete tumor regression, perhaps even curing some patients. This is an astounding feat in a setting where most therapies add only months to a few years in life extension for cancer patients. However, such drugs have performed poorly in other cancer types, including prostate cancer and pancreatic cancer.

Dr. Douglas Fearon, an immunologist at the University of Cambridge, UK, presented discoveries on how anti-tumor immune activity and the effectiveness of checkpoint inhibitor drugs are prohibited in mice with pancreatic cancer. Tumors are actually complex communities that house many populations of cells in addition to cancer cells. Most of these cell types are tumor-supportive, but anti-tumor immune cells can also get in and start killing tumor cells. To survive, tumors put into play those wicked strategies for turning off or keeping out interloper immune cells. The disparity of effectiveness of immunotherapies in different types of cancer indicates that various immune-system inhibiting strategies are in play. For instance, checkpoint inhibitors work in melanoma patients because they target what actually keeps the immune cells from working, while in pancreatic or prostate cancer, other mechanisms block immune cells from killing tumor cells, even with these therapies.

Fearon and colleagues found that in pancreatic tumors, tumor-supporting fibroblast cells make a molecule called CXCL12 that coats the outside of cancer cells, and prevents the presence of T-cells in the tumor. Fearon hypothesizes that when CXCL12 interacts with a molecule (CXCR4) on T-cells, this causes the T-cells to die, thereby protecting CXCL12-coated cancer cells. When mice were treated with agents that block this mechanism –by targeting either fibroblasts or CXCR4– T-cells could enter tumors and kill cancer cells. The addition of checkpoint inhibitor drugs on top of those treatments caused T-cells to be even better cancer cell-killers, indicating that these combination therapies may have significant clinical benefit in human cancer patients. Fearon is initiating a clinical trial that will test the efficacy of a drug (AMD3100) that inhibits CXCR4 in pancreatic cancer patients. Importantly, Fearon’s studies indicate that this immune-inhibiting mechanism also occurs in prostate, ovarian, and colorectal cancers. Studies are underway to validate if the same mechanisms are preventing checkpoint inhibitor drugs from working well in prostate cancer patients, and if similar combination treatment strategies are valid for each of these cancers.

Autophagy; a cellular activity that has dual roles in promoting and inhibiting tumors, might actually be a good therapeutic target

Dr. Ravi Amaravadi: “Autophagy and developmental therapeutics”

Autophagy is a multi-step process in which cellular components are broken down to be recycled by organelles called lysosomes. The activation of the autophagy process is intimately tied-in with immune responses, and studies have indicated confounding roles for autophagy in both promoting and inhibiting tumor growth and anti-tumor immune responses. Dr. Ravi Amaravadi, of the University of Pennsylvania, is questioning whether autophagy should be promoted or blocked for tumor treatment.

In normal cells, autophagy (recycling) is balanced with cellular growth and metabolism, and is thought to occur at a low level. If this balance is thrown off by stresses such as the cell-growth boosting activity of oncogenes, the cells might revolt, and die or stop growing, unless they can successfully rebalance how much recycling vs. growth occurs, a feat achieved by progressing tumors. Amaravadi hypothesizes that autophagy’s divergent roles in promoting versus inhibiting tumor growth can be explained by differing roles during different stages of cancer progression. In many advanced cancers, autophagy is elevated, indicating a role in promoting tumor cell survival.

Many anti-cancer therapies enhance autophagy. Amaravadi wanted to determine whether levels of autophagy were associated with therapeutic effectiveness of such drugs, which include BRAF-inhibitors. Tumor tissues from melanoma patients with a BRAF-mutation in their tumors (a mutation in the BRAF protein that causes it to be a melanoma-driving oncogene) and who had been treated with a BRAF-inhibitor, were assessed for levels of autophagy as compared to the patients’ clinical outcome. Patients with elevated autophagy in tumors had worse outcomes. When mice with melanomas were treated with an autophagy inhibitor in addition to a BRAF-inhibitor, tumor growth was slowed. The hope is that combining autophagy-inhibitors with other cancer drugs may improve patient outcome. Toward this, Amaravadi presented results from five early phase clinical trials that combined an autophagy inhibitor with various other therapeutics in a number of cancer types. Indications of clinical activity were observed with several combinations, and Phase II trials have been initiated to further explore how well these drugs work. Dr. Amaravadi and colleagues are also working to develop autophagy inhibitors with improved clinical activity.

Additionally, Amaravadi has been studying how autophagy can promote pro-tumor vs.anti-tumor immune activities. He presented findings that high levels of autophagy cause tumor cells to secrete a number of inflammation-associated proteins, which, like autophagy, have roles in both promoting and inhibiting anti-tumor immune activity under different contexts. Melanoma patients with high levels of autophagy in tumors had high levels of these proteins in their blood. Much more remains to be determined about the role of autophagy in cancer, including whether or not targeting different components of this multi-step process will have improved anti-cancer benefit, and further understanding how autophagy affects the tumor and the immune system.

Overall, many strides have been made toward understanding how the immune system becomes activated to recognize and kill tumor cells, and how tumors are able to escape from being killed by T-cells. Immunotherapies have had poor success thus far in prostate cancer patients, but this research presented at AACR will certainly pave the way toward new immunotherapeutic treatment strategies for men with prostate cancer. The fervent hope is that the cures that have been achieved in some melanoma patients by immunotherapies will soon be extended to patients with prostate and other cancers.

The 2014 AACR Annual Meeting was held from April 5-9 in San Diego, CA.

Andrea Miyahira
Dr. Andrea Miyahira has a PhD in cancer immunology, and is Director of Research at the Prostate Cancer Foundation.