Cancer is very complex disease characterized by an uncontrolled cell growth that often gives raise to malignant tumors and the ability to spread. A cancer cell is something like when Dr. Jekyll transformed into Mr. Hyde, the cell changes its appearance, behavior, metabolism and even its genetics1. Are we any closer to better treatments? I introduce to you immunotherapy, a new hope.
The problem with cancer is that evolves strikingly different depending on the tissue, patient age, tumor progression, genetic background and environmental factors. Due to this complexity we have not been able to develop effective therapies to treat it. Fortunately we are beginning to learning more details of the disease that may contribute to develop new therapies. This is the case for an emerging group of treatments called immunotherapy which takes advantage of the patient’s immune system to fight off cancer. A few decades ago not many scientists would have thought that our immune system could protect us against cancer. But how can our immune system distinguish healthy cells from cancer cells? Can we use the cancer cell signature to teach our immune system eradicate it? Here I give you some basics to understand how this works.
T-cells are the hitman of our immune system
Our immune system has many elements to confront the bad guys but there is a particular type of cells in the front line. Commonly known as T-cells, T lymphocytes patrol our body identifying unusual patterns called antigens or its derived fragments called epitopes, displayed in their surface of our cells. We can distinguish two subtypes of T cells; The CD8+ or cytotoxic cells interrogate any cell of our body for epitopes presented in a scaffold called MHC-I while the second subtype, CD4+ or helper cells mainly recognize epitopes displayed by a similar scaffold called MHC-II found almost exclusively in professional antigen-presenting cells (APCs).
Antigen-T cell interaction is a biological process finely tuned through the evolution. MHC scaffolds that hold epitopes are proteins encoded by the HLA genes (read more here). In humans HLA genes have a strikingly high mutation rate. But why? Isn’t it a “mutation” a bad thing? Well, it depends; sometimes mutations have a positive effect. Pathogens are also in constant evolution to survive, they undergo mutations some of them beneficial to avoid the host defenses to feed or reproduce. Thus our immune system is under constant pressure to adapt to these evolving pathogens. The high numbers of mutations in the HLA genes increase the chances of a new pathogen antigen to fit in the MHC proteins. If so, the antigen will be displayed to T cells, which will ultimately lead to cell death.
But not all T cells can recognize the antigen. Only a tiny fraction of T cells, may be just 1 out of 100 T cells, will become an active “hitman” against the hidden pathogen or malignant cell2. Only 1%! The reason for this stems from a recombination process of the gene encoding for the T cell receptor (TCR), which recognizes the epitope bound to the MHC scaffold (shown in the figure below). Similarly as for MHC molecules, this rearrangement of the TCR gene increases the chances of a cell to recognize the epitope-MHC complex.
Understanding this three party interaction, T cell-antigen-MHC, is crucial to develop new therapeutic strategies to treat cancer and other diseases. We have just begun exploring this area of knowledge and we are currently developing technologies that help us gaining more insights into the T cell cancer biology3. Thanks to new methods developed at Sine Reker Hadrup’s lab at DTU (Denmark) we can now produce MHC molecules capable of binding hundreds or thousands of predicted epitopes and detect with much more sensitivity how antigen-specific T cells respond to them4.
Cancer cells also follow Darwin’s principles
People think of cancer as a single disease that behaves similarly to an infection. However, there is much more behind. Cancer is a very dynamic disease, and like every living organism in nature cancer cells are subjected to evolution laws. What does this mean? Only the most adapted cancer cells survive in their environment. During transformation process to malignant, normal cells start changing their genetics and gene expression patterns, sometimes displaying new epitopes, known as neoepitopes, that wouldn’t be displayed in healthy cells or at least not at high levels. Our immune system might actually recognize them at first and try to target these cells. But interestingly enough, cancer cells find a way to escape this aggression from our immune system.
It is hypothesized that evolution drives this process within the tumor by selecting those cells capable of withstanding the attack. For example, some cells within the tumor may spontaneously display proteins that put T cells asleep, a process known as checkpoint inhibition. This is the case of the PD-1, a protein localized on the surface of T cells that inhibits them upon binding the partner protein PD-L15. The tumor microenvironment of certain cancer types seems to be enriched in PD-L1, putting the tumor in a stealth mode. These cancer cells with high levels of PD-L1 will survive and continue dividing following Darwin’s evolution theory principles as they can’t be eradicated it by our immune system.
Immunotherapy: a new hope
Using our knowledge of the immune system a new therapeutic area has emerged. Immunotherapy is the term to refer to this new group of treatments. Here I summarize some of the most widely used that showed promising results in clinical trials or already approved by the health authorities:
- Monoclonal antibodies: Antibodies are proteins naturally produced by B lymphocytes, bind a specific antigen and neutralize the threat. Typically therapeutic antibodies are produced biologically in large fermenters using expression mammalian cell hosts. Synthetic antibodies are recovered from the fermenter’s broth and subjected to a purification process that delivers a pure and safe therapeutic product. Rituximab is an example of this kind used to treat B cell cancers.
- Checkpoint inhibitors: As mentioned above cancer cells use T-cell checkpoints to escape from the attack. A whole new area of therapeutics is based on monoclonal antibodies that specifically block PD-1, PD-L1 and CTLA-4. In patients with melanoma and non-small cell lung cancer these treatments extended patient life up to 5 years in some cases. The first treatment called Nivolumab was approved in 2014 and 2015 by the American and European drug agencies respectively.
- Vaccines: Because our T cells may recognize specific cancer antigens, vaccines can be made out of synthetic neoepitopes. Personalized neoepitopes formulated in adjuvants can be injected into the patient in combination with other treatments6. Alternatively T cells from the patient are collected and stimulated with one a cocktail of neopeitopes in vitro before infusing them back into the patient. Stimulated T cells would then target cancer cells displaying the neoepitope. There are multiple ongoing clinical trials evaluating this approach that show positive effects of combination therapies using neoepitope vaccines and other chemotherapy agents.
- CAR Therapy: It means Chimeric Antigen Receptor (CAR) for T cells. Consist of genetically engineered T cell receptors with the binding parts of an antibody which both recognizes cancer cells and at the same time activates T cell. T cells can be collected from the same patient and manipulated to introduce the DNA encoding for the chimeric receptor CAR. The DNA is typically introduced using viral vectors, which is the main hurdle in the application of this therapy but has undoubtedly given very promising results, for example in treating leukemia as shown in the ARI project at the Hospital Clinic of Barcelona (Spain).
Why you should support this field
Immunotherapy may not be considered as a stand-alone therapy but it is proving to be an effective alternative to plain chemotherapy. Unlike chemotherapy, immunetherapy has fewer side effects, it is more customizable for the patient’s cancer type, and at the same time shows significant improvement in the survival rate. It is absolutely necessary that foundations, governments, companies, and charities keep supporting our research in this field. As a citizen you can become a hero demanding this support. We do not have to forget that by supporting research you contribute to a better quality life for patients and their families, which is the whole point of the research briefly summarized above.
1 Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646-674, doi:10.1016/j.cell.2011.02.013 (2011).
2 Karanikas, V. et al. High frequency of cytolytic T lymphocytes directed against a tumor-specific mutated antigen detectable with HLA tetramers in the blood of a lung carcinoma patient with long survival. Cancer research 61, 3718-3724 (2001).
3 Andersen, R. S. et al. Parallel detection of antigen-specific T cell responses by combinatorial encoding of MHC multimers. Nature protocols 7, 891-902, doi:10.1038/nprot.2012.037 (2012).
4 Bentzen, A. K. et al. Large-scale detection of antigen-specific T cells using peptide-MHC-I multimers labeled with DNA barcodes. Nature biotechnology 34, 1037-1045, doi:10.1038/nbt.3662 (2016).
5 Azoury, S. C., Straughan, D. M. & Shukla, V. Immune Checkpoint Inhibitors for Cancer Therapy: Clinical Efficacy and Safety. Current cancer drug targets 15, 452-462 (2015).
6 McGranahan, N. et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 351, 1463-1469, doi:10.1126/science.aaf1490 (2016).