Keywords

Introduction

In 1895, Wilhelm Konrad Roentgen described a novel radiation quality which he termed “X-rays” [1]. The importance of this discovery was immediately recognized by the scientific community and was spread rapidly across the globe. It reached Émil Grubbé in Chicago: a 21-year old student who was attending Hahnemann Medical School at that time. He was probably the first who used the novel radiation quality in a therapeutic setting in order to treat cancer–not even one year after Roentgen's discovery [2, 3]. This was the beginning of radiotherapy. In 1908, the first case report on what today would be classified as an “abscopal effect” of radiotherapy was published: A case of head and neck cancer described by H.D. McCulloch who also presented his hypothesis on how “immunity” contributed to spontaneous tumor regression upon irradiation of the “lymphatic glands” [4]. Since then, radiotherapy has gone through a series of impressive technical improvements and physical refinements and has evolved to a central treatment modality for various types of solid cancers, including head and neck squamous cell carcinoma (HNSCC) [5].

Radiotherapy and Immunotherapy in HNSCC Treatment

For locally advanced HNSCC, radiotherapy is implemented in definitive or adjuvant settings. State-of-the art techniques include intensity-modulated and volume-modulated arc treatment protocols in daily fractions of 1.8–2.0 Gy, alone or combined with concomitant chemotherapy [6, 7]. In recurrent or metastatic disease stages, immune checkpoint inhibition has emerged as a central part of the standard-of-care [8], together with the EXTREME chemotherapy protocol involving 5-fluorouracil, cisplatin/carboplatin, and cetuximab [9], and/or stereotactic body radiotherapy with high single doses and steep dose gradients as a palliative option [10].

Clinical responses upon immune checkpoint inhibition are impressive but remain limited to a minority of patients [11, 12]. Primary resistance of never-responders is considered to derive from host- and tumor-specific characteristics, the latter comprising immune checkpoint activity, tumor immune contexture, tumor mutational burden, (neo-)antigen load, and others (Fig. 2.1). Secondary resistance of initially responding patients in addition, appears to be driven predominantly by irreversible T-cell exhaustion and therapy-induced selection of tumor cell clones with mutations in critical genes involved in the immune checkpoint response [13, 14].

Fig. 2.1
A schematic representation of primary and secondary immune checkpoint inhibition resistance mechanisms demonstrates metastases in the lungs, a primary tumor in the chin, and immune checkpoint inhibition on the hand.

Mechanisms of primary and secondary resistance against immune checkpoint inhibition

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Immunological Effects of Radiotherapy

With particular focus on primary resistance against immune checkpoint inhibition, scientific interest of preclinical and clinical researchers currently aims at the development and evaluation of combined modality treatment approaches, for instance in combination with radiotherapy: Can the immune contexture be altered in order to convert immunologically cold tumors into hot ones? And can tumor-antigenicity be increased, for instance by enforcing the presentation of neo-antigens? In this regard, the immunological implications of radiotherapy and the anecdotally reported abscopal effects are of interest. It took nearly 50 years until a term was coined for H.D. McCulloch's initial observation, and it was Robert Mole who defined it: Abscopal effects are radiation effects at a distance from the irradiated volume but within the same organism [15]. Meanwhile, this rather general definition is being nearly exclusively used in (oligo-)metastatic tumor settings describing the phenomenon of tumor regression at out-of-field locations distant from the primary site of local (radio-)therapy. In-depth preclinical analyses have shown that the underlying driving force of this phenomenon is a (re-)activation of systemic anti-tumor immune mechanisms and the cancer immunity cycle [16]. Irradiated tumor and normal tissue cells stimulate the recruitment and activation of antigen-presenting cells (APCs) which capture tumor antigen, migrate to the draining lymph nodes, and prime tumor-specific T-cell responses, particularly CD8+T-cell responses, which finally contribute to local and distant lesion regression. The basic idea of this concept and pioneering preclinical data for its validation were provided by Sandra Demaria and Silvia Formenti. From their and others’ experiments with mouse tumor models in which irradiation of the primary tumor stimulated regression of a secondary out-of-field tumor in a T-cell-dependent manner, they concluded that radiation can generate an in situ cancer vaccine [17,18,19,20,21].

An effective cancer vaccine consists of tumor-specific antigens, i.e. tumor-associated antigens or neo-antigens, and immune cell activating adjuvants. Accumulating evidence suggests that radiotherapy can affect both (Fig. 2.2).

Fig. 2.2
A schematic representation of the determinants of tumor antigenicity and adjuvanticity and their modulation by radiotherapy. Evidence suggests that radiotherapy can affect the tumor-associated antigens or neo-antigens, and also the immune cell activating adjuvants.

Determinants of tumor antigenicity and adjuvanticity and their modulation by radiotherapy

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The irradiated state of tumor cells bears interesting analogy to the anti-viral state [22]. Fragments of nuclear and mitochondrial DNA that are released into the cytosol can stimulate cytosolic nucleic acid sensors to mount an intra-tumoral type I interferon response which is essential to (re-)activate the cancer immunity cycle and (re-)invigorate systemic anti-tumor T-cell responses [23, 24]. The optimal irradiation dose and regimen to trigger these mechanisms are still under debate and seem to reveal non-linear dose–response behavior. Both, super-hypofractionated protocols (i.e. 3 × 8 Gy) as well as low dose radiotherapy with single fractions of around 2 Gy were reported to be effective in this regard [25,26,27].

Apart from the intra-tumoral type I interferon response which essentially contributes to the maturation and activation of APCs in the irradiated lesion, cytosolic DNA fragments and persisting DNA damage also determine the overall cell fate in response to radiotherapy. This strongly shapes the adjuvanticity of irradiated cells as well. Whereas non-malignant cells with functional cell cycle checkpoints commonly undergo cellular senescence upon irradiation, tumor cells often fail to properly arrest in cell cycle until the damage is repaired. In consequence, they experience several rounds of aberrant mitosis and finally commit to cell death of different morphotypes [28,29,30]. Depending on a spectrum of physical and biological parameters, including radiation quality and dose, origin and genetic repertoire of the irradiated cells, and the functionality of cell cycle checkpoints, regulated forms of apoptotic or necrotic morphology can be observed. In tumors of epithelial origin, such as HNSCC, the regulatory machinery of apoptotic cell death is frequently perturbed, and different forms of regulated necrosis appear to be dominating in response to irradiation, including but not limited to necroptosis, ferroptosis, pyroptosis, and parthanatos [31, 32] which–although regulated via different signaling cascades–all share in common that the plasma membrane disintegrates and cellular contents are released [30, 33]. Danger signals and/or damage-associated molecular patterns (DAMPs) leaking out of the dying cells activate pattern recognition receptors on neighboring cells, endothelial cells, and immune cells, and trigger an immunological reprogramming of the tumor microenvironment [29, 30].

If cell cycle checkpoint function is operational, tumor cells can commit to irradiation-induced cellular senescence. Similar to irradiated non-malignant cells, they arrest in cell cycle, increase in size, and reshape their intercellular connections and stress fibers. They produce a wide spectrum of cytokines, chemokines, and growth factors, the so-called senescence-associated secretory phenotype or SASP, which exerts multiple effects in the tumor microenvironment [34, 35]. SASP factors can contribute to vascular remodeling and immune cell recruitment [26, 36]. On the contrary, they can also support cancer cell stemness, therapy resistance, tumor repopulation, and invasion [37, 38]. So, radiotherapy-induced senescence and the corresponding secretome present as double-edged swords which can precondition the tumor microenvironment for immune checkpoint inhibition and at the same time can drive (radio-)therapy resistance and tumor progression. Accordingly, the current discussion about the implementation of broad-range senolytic and/or senomorphic drugs in the context of multi-modal cancer therapy should also include selective targeting of distinct SASP cytokines [39, 40].

Apart from elevated tumor adjuvanticity, several reports have described increased tumor antigenicity upon radiotherapy originating from radiation-induced expansion of the major histocompatibility class I/II ligandome and the exposure of neo-antigens [41,42,43,44]. Collectively, radiotherapy thus may serve as a means of personalized in situ cancer vaccination which can synergize with immune checkpoint inhibition and may help to undermine primary resistance against immune checkpoint inhibition.

Clinical Experiences with a Combination of Radiotherapy and Immune Checkpoint Inhibition in HNSCC

Given that the mechanisms described above are operational, the (re-)activation of systemic anti-tumor immunity by a combination of radiotherapy and immune checkpoint inhibition in preclinical model systems can be reportedly achieved on a reliable and regular basis [21]. However, clinical experiences are different. Here, the description of abscopal tumor regression remains limited to scattered case reports and few retrospective analyses. Nevertheless, the first cases were described at the very beginning of the therapeutic application of ionizing irradiation, and their numbers appear to be increasing–particularly since the advent of immune checkpoint inhibition [4, 45]. The most prominent case of abscopal lesion regression upon radiotherapy with ongoing immune checkpoint inhibition was reported by Michael A. Postow and colleagues. It was a case of metastatic melanoma, in which upon progression during anti-CTLA4 treatment stereotactic irradiation at 3×9.5 Gy was applied to a paraspinal lesion. The irradiated lesion showed a good response, and interestingly also the non-irradiated splenic lesions did regress [46]. Similar case reports can be found predominantly for melanoma, lymphoma, and lung cancer [21]. However, corroborating these case reports by higher level evidence in a randomized phase II trial has failed so far–at least for HNSCC. Sean McBride and colleagues compared inhibition of programmed cell death protein 1 (PD-1) versus PD-1 inhibition plus concomitant stereotactic body radiotherapy in unselected patients with metastatic HNSCC, and the rate of abscopal effects was the primary endpoint (i.e. objective response rate of non-irradiated lesions) (NCT02684253). No evidence of abscopal effects and no improvement in response rates were observed [47].

Encouraged by the success of palliative immune checkpoint inhibition in relapsed and/or metastatic HNSCC, its concomitant addition to curative-intent radiochemotherapy for locally advanced HNSCC is currently being investigated [48]. Despite good tolerability, efficacy data reported so far are rather disappointing. As such, JAVELIN Head and Neck 100, the first randomized, placebo-controlled phase III trial adding concomitant PD-L1 inhibition to definitive radiochemotherapy in locally advanced HNSCC led by Nancy Lee did not meet its primary objective of prolonging progression-free survival [49]. Further randomized phase II and III trials evaluating the concomitant addition of PD-1/PD-L1 blockade to radiochemotherapy and/or radiobiotherapy (e.g. KEYNOTE-412 (NCT03040999) or GORTEC 2017–01 “REACH” (NCT02999087)) are still ongoing. Yet, reported interim analyses prognosticate that at least the latter may not change the current standard-of-care for locally advanced HNSCC.

Considering the successful implementation of adjuvant immune checkpoint inhibition in other cancer entities–yet with clearly different treatment schedules–these results are rather disappointing. In the randomized phase III PACIFIC trial (NCT02125461), Scott J. Antonia and colleagues compared inhibition of programmed cell death ligand 1 (anti-PD-L1) as maintenance therapy after radiochemotherapy versus placebo in patients with stage III non-resectable non-small cell lung cancer. For both co-primary endpoints of progression-free and overall survival, the immune checkpoint inhibition arm was clearly superior [50]. Similarly, adjuvant PD-1 inhibition was also successful in patients with esophageal or gastroesophageal junction cancer as reported in CheckMate 577 (NCT02743494), a randomized, placebo-controlled phase III trial led by Ronan J. Kelly [51].

The reasons underlying these discrepant trial results need to be investigated in order to refine and optimize treatment concepts and to develop radiochemoimmunotherapy protocols with improved outcomes for patients with locally advanced HNSCC. Obviously, different strategies of immune checkpoint inhibition (anti-PD-1 or anti-PD-L1 blockade) and different immunoglobulin G (IgG) classes with different epitopes were used. These reported disparities have an impact on efficacy and safety profiles [52]. Of note, JAVELIN Head and Neck 100, KEYNOTE-412, and GORTEC 2017–01 “REACH” all rely on targeting the ligand PD-L1 and not the receptor PD-1. This may have implications for tumor-cell-intrinsic, retrograde signaling of PD-L1 which has recently been reported to support tumor cell growth, stemness, as well as DNA damage repair, and thus may drive resistance against the concomitantly administered radiochemotherapy [53, 54]. Furthermore, the treatment sequences need consideration. Immune checkpoint inhibition with concomitant radiochemotherapy provided negative results in JAVELIN Head and Neck 100, whereas adjuvant immune checkpoint inhibition after completion of radiochemotherapy was used in the successful PACIFIC and CheckMate 577 trials. Preclinical studies in diverse cancer models had shown that simultaneous immune checkpoint inhibition (with or without a loading dose prior to the start of radiotherapy) was superior to the adjuvant treatment sequence [55], and thus guided the trial designs of JAVELIN Head and Neck 100, KEYNOTE-412, and GORTEC 2017–01 “REACH”. In this regard, the lymphotoxic effects of concomitant radiochemotherapy during immune checkpoint inhibition may need to be considered. Chemoradiation of the circulating blood pool as well as of the tumor draining lymph nodes may interfere with the successful release of immune checkpoints and may be of minor importance in the context of adjuvant or neoadjuvant immune checkpoint inhibition [56]. Accordingly, the question arises if sparing of the lymph nodes–at least in the early phase of immune checkpoint inhibition–or alternative treatment sequences could be beneficial. Combinations of radiochemotherapy with adjuvant or neoadjuvant immune checkpoint inhibition for locally advanced HNSCC are currently underway [48]. Another relevant parameter is the fractionation regimen of radiotherapy. As described above, preclinical data suggest that the synergism between radiotherapy and immunotherapy reveals a non-linear dose–response relationship, and the optimal fractionation protocol for the (re-)activation of systemic anti-tumor immune mechanisms is still under debate. Presumably, there is no “one-fits-all” regimen, and entity-specific characteristics may need to be considered [57]. Along these lines, unique and so far disregarded aspects of HNSCC biology and/or immunology may render the implementation of immune checkpoint inhibition into the standard-of-care with curative intent for patients with locally advanced HNSCC so difficult.

Conclusions

  • Immune checkpoint inhibition has emerged as an integral part of the standard-of-care for recurrent and/or metastatic HNSCC, but response rates remain limited to a minority of patients.

  • Mechanisms of primary and secondary resistance comprise tumor- and host-derived factors, including immune checkpoint activity, immune contexture, tumor mutational burden, neo-antigen load, and others.

  • Preclinical studies and clinical case reports have shown that radiotherapy can function as a means of in situ cancer vaccination to (re-)activate systemic anti-tumor immunity, to synergize with immune checkpoint inhibition, and to break primary resistance against immune checkpoint inhibition.

  • Evaluation in randomized clinical trials has provided heterogeneous results, particularly for HNSCC.

  • Scheduling and dosing of combined modality treatment regimens appear to be challenging.

  • Unique aspects of HNSCC biology and/or immunology may be responsible that the combination of radiotherapy and immune checkpoint inhibition is so difficult.