Surgery, radiation and chemotherapy have cemented themselves as the three core approaches for treating cancer but, a fourth strategy is now beginning to expand our arsenal of cancer therapeutics. Cancer immunotherapy stimulates the host immune system to attack and destroy cancerous cells using antibodies, small molecules, cells and viruses. This strategy of leveraging the immune system to treat cancer was first utilised in 1893 by the surgeon William Coley, now considered by many to be the “Father of Cancer Immunotherapy”. Following several disappointing efforts and clinical failures, the field of cancer immunotherapy has recently received a significant boost. First, the approval of the autologous cellular immunotherapy Sipuleucel-T for the treatment of prostate cancer in 2010. Then, the approval of the anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) antibody, Ipilimumab and of anti-programmed cell death protein 1 (PD1) antibodies for the treatment of melanoma in 2011 and 2014 respectively. All huge successes that helped to reinvigorate the field and demonstrate that immunotherapeutic approaches have a lot to offer across cancer types.
Targeting regulatory T cells
Recent successful antibody-based strategies have focused on enhancing anti-tumor immune responses by targeting immune cells, irrespective of tumor antigens. One recent study, led by a team at Brigham and Women’s Hospital, published in Science Immunology, demonstrated how regulatory T-cells (Tregs), which help the immune system to maintain tolerance of “self” can also prevent the immune system from detecting and targeting cancer cells. To combat this effect, the team targeted a molecular complex (latency-associated peptide complexed with transforming growth factor- β), uniquely expressed on the surface of Tregs, with anti-LAP antibodies. Their results showed that these antibodies could restore the immune system’s ability to fight cancer by increasing the activity of T cells and improving immune memory. The antibody-based approach was able to reduce tumor growth in models of melanoma, colorectal carcinoma and glioblastoma. To move this work toward the clinic the team will now be partnering with Tilos Therapeutics to modify the antibody for use in humans.
Recently published in Cancer Research, another study, led by researchers at the Medical University of South Carolina, has also demonstrated success with a Tregs-related approach. Specifically, they set out to block TGF-beta, a cytokine that controls the cell cycle used by Tregs to tell immune cells not to attack normal cells in the body. Malignant tumors release large amounts of TGF-beta allowing them to divide rapidly by causing Tregs to supress the immune cells that would otherwise fight them. Their strategy was to target GARP, the only known cell surface receptor that allows TGF-beta to dock on the surface of cells. Dr Zihai Li, Principal Investigator on the project, knew that GARP could bind and activate TGF-beta and then float off the surface of cells that express it. So, theyhypothesised that this may be how cancer cells store and release TGF-beta in vast quantities. By immunising mice with human GARP the team developed an antibody candidate, 4D3, that directly blocked TGF-beta from binding to GARP. Alone, they found that 4D3 could effectively prevent metastasis to the lungs in mammary gland cancer models. But, more excitingly they discovered that as part of a combination therapy with cyclophosphamide chemotherapy, 4D3 could curb both primary tumor growth and metastasis. Their results indicate that a GARP antibody treatment may be able to provide a significant boost to the standard chemotherapy utilised for treating breast cancer. In a press statement, Li said “This discovery is fundamentally important to how TGF-beta utilizes GARP to promote cancer and down-regulate the immune system, but it also creates an opportunity for both diagnostics and therapeutics”.
PD-1 inhibitors may work in an unexpected way
Directly targeting and boosting the immune system is not a new approach to cancer immunotherapy. In 2001, researchers found that cancer cells leverage the immune safeguard, PD-1, to ensure their growth. PD-1 is a cell receptor and “immune checkpoint”, that, like Tregs, plays a crucial role in preventing the immune system from becoming overactive and damaging the body. Following this discovery, antibodies were developed to block the PD-1 receptor or its binding partner, PD-L1, which are now common place in cancer care.
Now, a team at Stanford University, have uncovered a novel mechanism by which these PD-1 inhibitors may act to fight cancer. In a recent Nature paper, they demonstrated how these drugs may also prompt macrophages to engulf and destroy cancer cells. Their findings show that PD-1 activation not only inhibits the activity of T-cells but, also prevents the anti-cancer activity of macrophages. In a press statement, Lead Author, Dr Sydney Gordon said, “Macrophages that infiltrate tumors are induced to create the PD-1 receptor on their surface, and when PD-1 or PD-L1 is blocked with antibodies, it prompts those macrophage cells to attack the cancer”.
The researchers do accept that it’s currently unclear to what degree macrophages are involved in the success of anti-PD-1 and anti-PD-L1 antibodies. That said, Gordon believes that the implications of the study could be significant stating that, “This could lead to novel therapies that are aimed at promoting either the T-cell component of the attack on cancer or promoting the macrophage component”. The team also believe that antibodies to PD-1 or PD-11 could be more potent and broadly applicable than previously conceived. Senior Author, Professor Irving Weissmann explained “For T cells to attack cancer when you take the brakes off with antibodies, you need to start with a population of T cells that have learned to recognize specific cancer cells in the first place. Macrophage cells are part of the innate immune system, which means they should be able to recognize every kind of cancer in every patient.”
Making cancer curable
Cancer immunotherapy is at a critical and exciting stage fuelled by developments in high-throughput genetics, bioinformatics, imaging and analytical technologies. Alongside major funding boosts from sources such as NCI, Cancer Research UK and from within big pharma. So far, most of the clinical success in the immunotherapy landscape is based on checkpoint modulatory antibodies, but this success is anticipated to expand to other modalities, as well. If the current excitement continues, novel immunotherapeutic agents have the potential to transform cancer into a truly curable disease.