From BiTEs to CRISPR-CAS and from miRNAs to ZEB1. From AI to next-generation sequencing and from PD-1 inhibitors to T-vec oncolytic viruses. The future of cancer immunotherapy is here, and it is promising. While significant progress has been made since Richard Nixon declared the War on Cancer in 1971, the aim of reducing overall mortality proved more difficult than anticipated. For decades, much if any hope for something approximating a specific cure seemed futile. Today, however, steadfast progress is being made on many novel fronts. Perhaps the most promising of these is immunotherapy. Here I will discuss the state-of-the-art and future promise of various forms of cancer immunotherapy. I will argue that a definitive victory is - to a significant extent - a matter of time. The battle, however, is undoubtedly going to be a long haul that involves not years but many decades, at the very least.
Immune checkpoint inhibitors
Probably you’ve come across these acronyms somewhere before, even if at the time your eyes glanced over them: PD-1, PD-L1 and CTLA4. Never mind what they stand for since what they do is much more important. PD-1 et al. are cell-surface proteins, involved in a process called checkpoint inhibition.
One of the most important principles of an effective but viable immune system is the discrimination between self and non-self. In principle, our immune systems ought to attack only that which is foreign. One way of achieving this is via immune checkpoints. They provide a mechanism via which immune cells are inhibited from attacking our own cells, thus preventing autoimmunity.
Tumor cells are known to elicit both local and systemic immunosuppression via a variety of mechanisms. One of these is the upregulation of PD-L1 expression on the surface of tumor cells, which then engages with PD-1 on cytotoxic T-cells, inducing their apoptosis. By blocking the interaction between PD-L1 and PD-1, this inhibitory immune checkpoint is consequently abolished. The cytotoxic T-cell response is then allowed to recommence, killing the aberrant cells in the process.
Besides PD-1, other immune checkpoints such as CTLA-4 are being exploited. IDO is a particularly interesting target that is currently being researched. Indications include melanoma, lung cancer and Hodgkin’s lymphoma.
T-cell engineering
In 2015 Siddhartha Mukherjee (author of The Emperor of All Maladies) gave a TED talk called ‘Soon We’ll Cure Diseases with a Cell, Not a Pill’. In it, he talks about how the amazing success of antibiotics created a distortion in our thinking about medicine. According to Mukherjee, what is needed today is a paradigm shift away from the medication-centred conception of medicine, towards one that stresses alternative strategies to cure diseases. Examples of such strategies focus on exploiting living cells or altering the environment in novel ways.
One example of such a strategy is to enhance the cancer-fighting abilities of T-cells. By combining adoptive T-cell transfer and genetic engineering modified T-cells can be produced, known as chimeric antigen receptor T-cells (CAR T-cells). CAR T-cells are strongly superior in detecting aberrant tumor cells compared to wild type T-cells.
CAR T-cells are chimeric because their receptor combines an outside antigen recognition domain with an intracellular T-cell signalling domain. The antigen recognition module usually consists of a single chain encompassing antibody variable heavy and variable light chains. This is a major upgrade compared to wild type T-cells, since the affinity of antigen recognition is enhanced by several orders of magnitude. Newer generations of CAR T-cells also incorporate various costimulatory domains.
Normally, T-cells recognize tumor antigens by having fragments of antigens presented to them on a serving platter called the major histocompatibility complex (MHC). CAR T-cells are not MHC-restricted: they are able to detect tumor antigens without the need for MHC presentation. This allows the CAR T-cells to detect a larger variety of tumor antigens, not only peptides but carbohydrates and inorganic compounds as well. Thus, the repertoire of potential tumor cells against which the CAR T-cells are able to react is vastly expanded. In addition, tumor escape mechanisms related to loss of MHC are simply bypassed.
Several strategies to improve the CAR T-cells even further are currently being devised. One example called TRUCK (T-cells redirected for universal cytokine-mediated killing) appears especially promising against solid tumors. TRUCK enables the T-cell response to attract innate immune cells via anti-tumoral cytokines directed against antigen-negative tumor cells, which normally would escape the CAR T-cell onslaught. Current indications for CAR T-cell therapy include acute lymphoblastic leukemia and diffuse large B-cell lymphoma.
The future of cancer therapy
The future for cancer therapy seems quite bright, since the many avenues of potential treatment options opened up by immunotherapy, allow for a great many upgrades, combinations, and novel strategies to still be devised or improved upon. Novel ways of gene modulation or genetic engineering present opportunities to overcome primary or secondary resistance against immune checkpoint inhibitors, increase sensitivity to chemotherapies, or even inhibit the processes underlying metastasis. The silencing of crucial epithelial-to-mesenchymal transition genes such as ZEB1, using various miRNAs, offers but one exciting opportunity. Even wilder opportunities are presented via synthetic biology or nanotechnology. Indeed, it may be that CAR T-cells are just the beginning in our journey of creating a whole host of novel synthetic immune cells capable of attacking cancer in unprecedented ways.
In principle, the ‘War on Cancer’ is one that can be won. To see this, it is crucial to understand that the battle against cancer is really a battle against evolution. Much like the fight against infectious disease involves a constant and continuous battle against novel evolutionary adaptations arising out of the processes of mutation and selection, so the fight against cancer involves rapidly mutating tumor cells being selected out of tumor populations via various therapeutic and immunological onslaughts. A crucial difference, however, is that infectious diseases have potentially unlimited time and opportunity to evolve outside of the confines of the human body, whereas cancer cells are constrained by it. It follows that given a sufficient amount of pressure put against tumor cell’s survival and reproduction (while simultaneously sparing the host), these cells will at a certain point no longer possess the time and opportunity necessary to evolve their way out of the onslaught. Fatalists who claim that a cure for cancer will never be found are missing the point, save insofar they're alluding to the truism that the cure for cancer doesn’t exist. Many if not most cancers will yield eventually - such is only a matter of time.
Of course, what exactly constitutes a 'matter of time' is impossible to say and will vary from cancer to cancer, from subtype to subtype and even from person to person. Suffice it to say that it is a long war undoubtedly involving not years but many decades, at the very least. Any hopeful prediction offering x number of years before we reach this or that cure are tendentious at best and immoral at worst. In the meantime most progress probably resides in neither cells nor pills, but from drastic changes to our carcinogenic environments. As put succinctly by Robert Weinberg: "If those two factors [smoking and obesity] can be changed in our society, we are going to see decreases in cancer mortality, at least over the next decade or two, that dwarf anything I and my colleagues can produce in terms of new miraculous cures." It seems the most miraculous cure of all, therefore, has always already been right before our very eyes.