Factors affecting tumor responders and predictive biomarkers of toxicities in cancer patients treated with immune checkpoint inhibitors
Introduction
Cancer patients at their early disease stage are more likely to well respond to most of conventional regimens with a favorable prognosis, whereas those with an advanced disease do not. Immunotherapy is a novel approach developed in the last decade and approved by the United States Food and Drug Administration (FDA) to treat advanced malignancies, which eradicates cancer cells by reinvigorating immune system, activating tumor antigen-specific cytotoxic T lymphocytes (CTLs) with improved clinical outcome in cancer.
Emergence of immune checkpoint blockades opens a new era of cancer therapy. 2018 Nobel Prize in Physiology or Medicine in the discovery of cancer therapy by inhibition of negative immune regulation further ignites enthusiasm to immunotherapeutic for more cancer types [1]. Monoclonal antibodies (mAbs) targeting CTLA-4, PD-1, or PD-L1 have received considerable and broad interest because of their ability to exert endurable clinical response in many first- and second-line regimen-refractory cancers [2], [3], [4]. Some patients generated abiding responses and therefore their survival was improved [5]. Anti-PD1/PD-L1 mAbs increase overall survival (OS) compared to the standard of care in different tumor types. These immune checkpoint inhibitors (ICIs) truly revolutionize the treatment of cancer patients particularly with an advanced disease [6], [7]. Nonetheless, the response rates still remain relatively low [4], [8]. Some patients initially respond to ICI therapy, but develop resistance after relapse [9], [10], [11]. A certain proportion of patients still have a progressive disease in spite of initial response [12], and others do not respond at all [9]. The proportion of patients in the United States who are eligible for these ICIs is approximately 44%, while around 13% respond to these ICIs [4].
Presently, ICIs in combination are being extensively evaluated for potential clinical benefit in a large number of tumor histology. Due to positive outcomes in preliminary trials, nivolumab plus ipilimumab is one of the most enthusiastically investigated combined immunotherapy regimens. Among many cancer types, melanoma is the one with a high response rate to the ICI therapy [13], [14]. On Oct. 22, 2018, Bristol-Myers Squibb (BMS) Company announced that the four-year Phase III CheckMate-067 clinical trial with three arms showed more endurable, long-term survival benefits with the combination of Nivolumab and Ipilimumab versus either Nivolumab or Ipilimumab alone in patients with advanced melanoma [15], [16]. With a minimum follow-up of 48 months, the four-year OS rates were 53% for the Nivolumab plus Ipilimumab in combination, 46% for Nivolumab alone, and 30% for Ipilimumab alone. Additionally, the percentage of the patients experiencing a complete response (CR) was 21% for Nivolumab plus Ipilimumab, 18% for Nivolumab alone, and 5% for Ipilimumab alone [16]. This result suggests that inhibiting both CTLA-4 and PD-1/PD-L1 could synergistically reactivate T cells and were beneficial to patients [17]. Consequently, the combination of the two regimens enhances the efficacy. Indeed, the more recently published results revealed that the combination of Ipilimumab and Nivolumab had a significantly better Progression Free Survival (PFS) compared to chemotherapy in NSCLC [18], with a 42.6% PFS rate for the immunotherapy combo compared to a 13.2% for chemo. Accumulating clinical trial data validate the benefit and rationale of this combinatorial immunotherapy as a powerful new treatment modality for the treatment of cancer.
The most successful immunotherapy to date is the blockade of the immune checkpoints PD-1 and CTLA-4 [19]. However, immune checkpoint blockade can lead to immune-related adverse events (irAEs) that affect any organ system with various clinical presentations. Most of the irAEs are mild, but some are severe and could result in the withdraw of immunotherapy, morbidities or even death. A meta-analysis of 112 clinical trials involving 19,217 patients who received ICIs showed the toxicity-related fatality rates of 0.36% (anti-PD-1), 0.38% (anti-PD-L1), 1.08% (anti-CTLA-4), and 1.23% (PD-1/PD-L1 plus CTLA-4), respectively [20]. There's been a lot of fanfare about the efficacy of the ICIs, but less attention has been paid to the occurrence, prevention, prediction of irAEs, and the resistance mechanisms. Early recognition and treatment of these irAEs represent an important clinical challenge for Oncology physicians. Clinicians across disciplines should not be unaware of these uncommon lethal complications. This article presents the existing toxic evidence related to ICIs, factors influencing tumor responders, prediction and treatment of these irAEs, as well as the new mechanisms of resistance to ICI therapy.
Section snippets
T cell exhaustion and T cell anergy
The immune system consists of innate and adaptive immunity. The innate immune cells target invaders at the first sign of infections or inflammation. Adaptive immune cells, including T cells, recognize and attack specific antigens. Immune evasion is a strategy used by cancer cells to escape host's immune attack, which involves a number of mechanisms, including such as T-cell exhaustion, immunosuppressive cytokines that “cool down” the immune system. T cell exhaustion is a state of T cell
Mechanism of CTLA 4 and PD-1/PD-L1 inhibition
The immune system produces an appropriate immune response against pathogens and cancer. T cell activation plays a pivotal role in killing pathogens and tumor cells. We have reported that T cell activation score, which summarizes weighted average of exhaustion- and activated-related gene expression, is positively associated with patient survival in breast cancer [26]. T cell exhaustion, which is characterized by progressive loss of T cell function, leads to poor prognosis. Recent evidence
Immune checkpoints on activation of anti-tumor immune response
Both the CTLA-4 and PD-1 can participate in T cell dysfunction, but they do not have exactly the same impact on immune system homeostasis, as demonstrated in murine models [34]. CTLA-4 and PD-1 act at different times in the cancer-immunity cycle. CTLA-4 limits T-cell responses early in immune response, primarily in lymphoid tissue; PD-1 limits T-cell response later in immune response, primarily in peripheral tissues. CTLA-4 expressed by T cells and PD-1 expressed by both T cell and other immune
Mechanisms of the ICIs against cancer
Immune checkpoints are actually a normal part of the immune system with the role of preventing immune response from being too strong to destroy healthy cells in the body. Certain protein receptors located on the surface of T cells help distinguish healthy cells from cancer cells. Current ICIs target CTLA-4 and PD-1 receptors. The PD-1 and PD-L1 is a receptor-ligand system and in tumor microenvironment, their engagement results in the blockade of anti-tumor immune responses [47]. PD-1 is mainly
ICIs and their adverse effects
To date, the US FDA has approved seven ICIs as shown in Table 1. Ipilimumab, the first one approved by the US FDA in 2011, targets CTLA-4. From then, several ICIs have been granted marketing authorization. The US FDA approved the second ICI Nivolumab in 2014, which targets PD-1. Combination of Ipilimumab and Nivolumab was approved in 2015. Atezolizumab is the third ICI approved by the US FDA in 2016, which target PD-L1. Pembrolizumab is the fourth ICI that target PD-1 with the US FDA approval
Occurrence of ICI-mediated toxicities and treatment
CTLA-4 and PD-1 immune checkpoints are negative regulators of T-cell immune function, and their expression on T cells leads to immune inhibition. Inhibition of these checkpoints results in an increased activation of the immune system. ICIs including the drugs Ipilimumab that targets CTLA-4 acts as a type of “off switch” on T cells, Pembrolizumab, Nivolumab and Cemiplimab against PD-1 that prevents T cells from recognizing and attacking inflamed tissues and cancer cells. Atezolizumab, Avelumab
Response rates and biomarkers for responders to ICI therapy
As a clinician, it is important to know who will and who will not gain benefit from potential ICI therapy. To determine the percentage of cancer patients who could potentially gain benefit from an ICI drug, Alyson Haslam et al. used annual cancer deaths as a stand-in for annual incidence of advanced or metastatic disease. The results showed that the estimated percentage of patients in the US with cancer eligible for ICIs was 26.86% (95% CI, 1.51–1.57%) in 2015 and increased to an estimated
Mechanisms of resistance to ICIs
Mechanisms of resistance to ICI therapy including innate and acquired resistance are not fully understood. However, durable responses suggestive of long-lasting immunologic memory are commonly observed in large subsets of cancer patients treated with ICIs [90]. Failure of ICI therapy can result from the defects in any of the types as follows: (1) insufficient generation and infiltration of anti-tumor T cells, (2) inadequate function of tumor-specific T cells, (3) impaired formation and
Factors influencing tumor responders treated with ICIs
Some clinicopathological factors such as sex, age, tumor size, and stage, etc. are also predictive markers of ICI therapy. In general, male patients have significantly longer PFS and OS than those female patients [104], and cancer patients whose age between 60 and 75 correlated with better ORR to ICIs [105], [106]. Tumor size is an independent factor that correlates with better ORR and OS for the cancer patients treated with ICIs [107]. In addition, there are some biomarkers that are helpful to
Predictive biomarkers of irAEs
Current ICI therapy has significantly improved the outcome of cancer patients, although the efficacy of the ICI therapy still remains limited. In particular, the therapy only works for a small portion of the cancer patients. Importantly, ICI therapy is also associated with substantial toxicities. Therefore, in order to avoid overtreatment of ICIs and minimize the irAEs development, predictive markers of the irAEs occurrence are important and required [127].
Like the factors that influence tumor
Concluding remarks and outlooks
Over the last decade, cancer immunotherapy has emerged as an attractive addition and alternative to conventional treatment strategies. ICI therapy opens an avenue of cancer immunotherapy with a potent clinical efficacy and prolongs survival in responder patients with cancer. Despite these promising long-term responses, the majority of cancer patients failed to respond to ICI-therapy with primary resistance. More importantly, some of cancer patients have to stop ICI therapy due to irAEs.
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