From the Zeno's paradoxes to novel immunotherapeutic agents for kidney cancer: moving from an era of wrong premises and conclusions to a better comprehension of immunology

Abstract

In the 5th century B.C., Zeno of Elea offered arguments that led to conclusions contradicting what we all know from our experience. The arguments were paradoxes for the ancient philosophers and it took centuries to demonstrate that they were not true. For example, in his Achilles and the tortoise paradox, fast running Achilles races to catch a slower tortoise that has a head start; so, if Achilles hopes to overtake the tortoise, he must run first to the place where the tortoise presently is, but by the time he arrives there, it would have crawled to a new place, so then Achilles must run to this new place, but the tortoise meanwhile will have crawled on, and so forth Achilles will never catch the tortoise, concludes Zeno. From this well known paradox, it appears clearly that from wrong premises come wrong conclusions, something that for years has affected our perception of the role of immunotherapy in kidney cancer.

Keywords::

• immunotherapy
• interferon
• interleukin-2
• kidney cancer

Which are these wrong premises?

The very first relates to the mechanism of action of immunotherapy.

For years we have oversimplified it, irrespective of the agent used, of its dose and of its route of administration.

Interleukin-2 (IL-2), for example, does not simply stimulates cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells, but exerts its antitumor activity through different and still ill-defined mechanisms [1].

For example, we still do not know if hypereosinophilia, which is often observed during IL-2 treatment, does play a role or not [2-5]; furthermore, only seldom in the history of immune therapy for cancer, other biological effect of IL-2 have been considered, even though they could theoretically account for both the antitumor activity, as well as for the toxicity profile, of this agent [1].

This is the case, among the other, for the production of reactive oxygen species [6-8], which indeed appears to be dose- and schedule-dependent [7,8], or to perturbations of the cell cycle [9].

Not to take into account, another huge paradox; as once provocatively stated by Prof. Carlo Buzio, one the believers of low-dose s.c. IL-2 treatment in kidney cancer, the immunotherapeutic agent IL-2 has been used with the same principles of chemotherapy, looking to the identification of maximum tolerated dose and responses, and not to its minimally biologically active dose and to disease stabilization.

Furthermore, authors have argued that IL-2 may not be the optimal T-cell growth factor in vivo, since, through the signaling of the high-affinity IL-2 receptor, it may stimulate and expand CD4⁺CD25⁺(FoxP3⁺) T regulatory cells (Treg), which in turn may suppress antitumor immune responses [10]; if so, other γc-signaling cytokines (e.g., IL-15), could be considered as more reasonable alternative choices for the immunotherapy of cancer [10].

The situation for interferon (IFN) is even worst, considering that even today we still do not exactly know how it works as an anticancer agent [1,11]; is it just a matter of immune modulation, or does it exert direct antiproliferative effects? And, if it is just a matter of immune stimulation then which all are its target cells? And finally, should we consider IFN as an antiangiogenic agent, according to its dose, as recently suggested by a randomized Phase II study of sorafenib plus two different schedules of IFN in kidney cancer [12]?

All these questions are all but trivial, since without this level of insight, we will continue to draw wrong conclusions from wrong premises.

Let's go back for a while to the studies performed in kidney cancer by the French Immunotherapy Groups and, in particular, to the Percy Quattro study published in 2007 [13].

In this study, advanced kidney cancer patients were randomized in a 2 × 2 factorial design to receive medroxyprogesterone acetate, IFN-α, subcutaneous IL-2 or a combination of both cytokines. The primary endpoint of the study was overall survival, while tumor response was evaluated at week 12 and month 6; finally, progression-free patients received further identical treatment for a maximum of 3 additional months. Since, there were no significant survival differences between IFN-treated patients and non-IFN treated patients or between IL-2-treated and non-IL-2-treated patients, while grade 3-4 toxicities were significantly more frequent in cytokine-treated patients than in medroxyprogesterone-treated patients, the authors concluded that immunotherapy is contraindicated in kidney cancer patients from the intermediate risk group [13]. The same group had previously demonstrated that immunotherapy is contraindicated in patients with poor prognostic features [14], again due to a combination of excessive toxicity and lack of survival benefit.

As a whole, according to these results, 75% or more of advanced kidney cancer patients should be regarded as ‘unsuitable for cytokines’, with further caveats also for good risk patients [15].

However, again, these look as wrong conclusions, deriving from wrong premises, the latter being represented by the assumption that the dose of the immunotherapeutic agents (and of IL-2, in particular) does not matter.

It does matter, and a lot.

Indeed, from other studies we know that lower doses of s.c. IL-2 do induce almost the same amount of immunological effects [16-18], with a completely different and better safety profile. Unfortunately enough, these observations come mainly from non-randomized studies [1], leading to the second wrong premise, i.e., the way immunotherapy has been clinically developed over time.

Very few randomized controlled trials of immunotherapy have been indeed performed in kidney cancer and the vast majority of those few were hampered by non-ideal designs, wrong (e.g., overall response rates) or relatively irrelevant endpoints (e.g., the validation of CAIX as a biomarker in the recent SELECT IL-2 trial) [19] and lack of immunological insight.

This made us forgetting one smart observation made by the late Prof. Pieter De Mulder, who used to highlight that Oncology is made by tails, … the tails of survival curves.

And indeed, all the above wrong premises made us also forget that, irrespective to the immunotherapeutic agent used, a small proportion of long-term survivors were commonly observed in cytokine-treated kidney cancer patients.

They are there, in the tails of the survival curves of the historical series of patients treated (mainly with IFN) at MSKCC [20], or in the tails of survival curves of patients treated with high-dose i.v. IL-2 at the NCI [21].

Have really these patients been cured by immunotherapy? Nobody knows for sure, but for years we underestimated these tails, being unable to understand clinical or immunological characteristics of these fortunate patients.

And this leads to the ultimate wrong premise, the mother of all wrong premises in this complex field: the lack of an adequate understanding of the mechanisms of antitumor activity (and of resistance to immunotherapy).

But fortunately enough, as Bob Dylan sung in 1964: the times they are a-changin’, which indeed was the title of the commentary accompanying the publication of the Percy Quattro study [22], at the very beginning of the targeted agents era.

This time, however, the new era is that of novel, mechanistically oriented, immunotherapeutic approaches.

Indeed, nowadays, our knowledge and comprehension of the complex mechanisms of immune response, as well as of immune evasion, are far more defined and refined, leading to the development of more biologically targeted immunotherapeutics.

In particular, negative regulators of the immune system, called immunologic checkpoints, have been found to play important roles in restraining otherwise effective anti-tumor immunologic responses. Therapies that target these negative regulator checkpoints, such as those directed against cytotoxic T-lymphocyte antigen 4 (CTLA-4) [23] and programmed death 1 receptor (PD-1) [24], have demonstrated exciting clinical results, especially the anti-CTLA-4 antibody ipilimumab in malignant melanoma [25].

Since it is possible that, in kidney cancer, we simply cannot further improve the results achieved so far targeting directly or indirectly angiogenesis, it is possible that the next step forward in this exciting field could be represented by novel, and more sophisticated, forms of immunotherapy, including checkpoints regulators or vaccines, as thoroughly discussed in this issue of Expert Opinion on Biological Therapy [26].

Declaration of interest

The authors state no conflict of interest and have received no payment in preparation of this manuscript.