Are immunotherapies really revolutionary, and what do they tell us about
immune–cancer interactions? From a strictly medical point of view, this enthu-
siasm is justified, although we should keep in mind that some important limits
exist. Thefirst limit is the low percentage of responders: less than 15 percent on
average, though it depends on tumor type and on the category of immunother-
apy ( Haslam and Prasad 2019). (Future research likely will significantly extend
the proportion of responders.) A second limit is the existence of sometimes
significant adverse effects (immunotherapies, in particular, increase the level of
inflammation and autoimmune responses, which can lead to colitis, hepatitis,
etc.) (Postow et al. 2018). A third limit is the currently exorbitant cost of some
treatments.
From a conceptual viewpoint, therapies based on immune checkpoint
inhibition constitute indeed a radical change in perspective (Lesokhin et al.
2015; Sanmamed and Chen 2018). At least two important features of
immune checkpoint therapies are worth emphasizing. First, the target of
the treatment is the immune system, not the tumor itself (as was the intention
with traditional treatments such as surgery, chemotherapy, and radiotherapy–
although, in fact, some of them are now known to act at least in part via
stimulation of the immune system (Galluzzi et al. 2012)). Second, the
objective is tobreak the state of immune tolerancethat has been established
between the tumor and the immune system in the local tissue (Lesokhin et al.
2015;Ribas and Wolchok 2018)–partly as a consequence of the chronic
expression of cancer antigens (Pauken and Wherry 2015). More precisely,
the aim with immune checkpoint blockers is to downregulate inhibitory
signals in tumor–immune interactions. This constitutes a move from
enhancement of the immune system to “normalization” of the immune
system: in immune checkpoint inhibitor-based immunotherapies, especially
with anti-PD-L1, the aim is not, strictly speaking, to boost the immune
system beyond its normal rate of activation but to restore a local context in
which the immune system will be able to act as it normally does (Sanmamed
and Chen 2018).
Together, basic studies about the role of the immune system in cancer and
clinical studies in the domain of immunotherapies also have contributed to an
important change in perspective about what cancer is and how it develops
(Prendergast 2012). It is increasingly recognizedthat tumor-centric views of
cancer (with genetic mutations seen asthe main cause of cancer) are insuffi-
cient: to understand (and cure) cancer, it is essential to consider not only the
tumor itself but also the tumor environment ((Bissell and Hines 2011;
Maman and Witz 2018); for conceptually and philosophically-oriented ana-
lyses, see (Bertolaso 2016; Laplane 2016; Plutynski 2018)). The tumor
36 Elements in the Philosophy of Biology