In recent years, immune therapies that develop and strengthen the power of the patient’s immune system to act against tumor cells are defined as the “fifth pillar” of cancer treatment. Immunotherapy, believed to be the most promising form of cancer treatment since the emergence of chemotherapy, is now being celebrated as a top advancement in cancer care. Encouraging clinical trial results involving the use of immunotherapy continue to yield more approved indications for various cancer types. This short review tries to present the most important advances in immunotherapy for solid tumors.
Immunoterapy in non-small cell lung cancer
Non-small cell lung cancer (NSCLC) is the leading cause of cancer death in the world(1). Over the past decade, new treatments have improved the survival of patients with advanced NSCLC and especially those with adenocarcinoma(2-5). For patients with advanced tumors containing EGFR activating mutations, targeted agents, called EGFR-tyrosine kinase (EGFR-TKI) inhibitors, may improve overall survival (OS) by about 20 months(6-9). Despite these improvements, few innovative NSCLC treatments with squamous histology have emerged, especially following the failure of first-line chemotherapy(10). A new class of drugs, called check point inhibitors, appeared as promising therapeutic options for these patients(11).
As a general model, tumor cells acquire more mutations during their development. These mutations can enhance aberrant proliferation and confer immortality on tumor cells. At the same time, some of the mutations produce aberrant proteins on the cell surface, which can serve as neoepitopes recognized by the immune system(12). Not all tumors have the same burden of somatic mutations and it is believed that the burden of larger tumor mutations leads to greater immunogenicity(12). Squamous NSCLC, as well as melanoma have the greatest burden of mutations among several solid tumors studied and they were the two types of cancer to be treated with immune control site inhibitors(13). The immune system is capable of recognizing and destroying tumor cells, as well as pathogens. However, one of the hallmarks of cancer is its ability to avoid the immune system(14).
There are a lot of complex interactions between the cells presenting the antigen, the lymphocytes and the tumor cells. The most studied is the cell membrane T cell receptor binding, called cell death 1: PD-1, and ligands 1 or 2 (PD-L1 or PD-L2), expressed by some tumor cells. This interaction results in the inactivation of T lymphocytes in an effort to avoid the immune response against tumor cells(11,12). The inhibition of this pathway is the target of inhibitors of immune control points. There are two types of agents: anti-PD-1 and anti-PD-L1 monoclonal antibodies.
Among these, anti-PD-1 agents that bind the lymphocyte receptor and block both PD-L1 and PD-L2 binding are considered to be more toxic than anti-PD-L1 due to their broad spectrum of clinical activity. However, this has not been confirmed by recent clinical trials(15,16). Pembrolizumab and nivolumab, two monoclonal antibodies against PD-1, as well as avelumab and atezolizumab antiPD-L1 monoclonal antibodies showed consistent anti-tumor activity against NSCLC(17-29).
Predictive biomarkers for the choice of treatment can improve efficiency and reduce costs, while eliminating the potential negative effects of unnecessary treatment(30,31).
For inhibitors of immune control, PD-L1 expression has been suggested as a potential predictive biomarker.
Immunotherapy in malignant melanoma
Advanced malignant melanoma was one of the first solid tumors in which immunotherapy was attempted and proved to be useful in advanced, inoperable or metastatic cases that did not have the BRAF gene mutation. In 2011, FDA approved ipilimumab for the treatment of advanced malignant melanoma (AMM). In 2104, pembrolizumab was approved as monotherapy, and then the combination of nivolumab-ipilimumab. Adjuvant therapy with nivolumab or pembrolizumab has also been approved. In the prospect, pembrolizumab is expected to be an adjunct therapy for ipilimumab plus nivolumab(32).
Immunotherapy of renal cancer
High doses of interleukin-2 (IL-2), as an initial form of immunotherapy used for renal cell carcinoma, were the first immunotherapy trials in renal cancer. The use of this drug has helped to elucidate that there are factors in the immune system that can be harnessed in a percentage of patients which can be used in treatment. More recently, with the discovery of ligands and receptors for “control points” such as PD-1/PD-L1 and CTLA4, it has become increasingly clear that by blocking certain immune-cellular interactions, the immune system can be used to help kill malignant cells.
There are immunotherapy agents that are now approved for the treatment of metastatic renal cell carcinoma. Nivolumab was the first drug to be approved by the FDA based on the Checkmate 025 study comparing everolimus with nivolumab and showed a better objective response rate in patients who had received nivolumab (HR 5.98; p<0.0001) with a continuous response at 44%.
One of the current and future study pathways for immunotherapeutic agents is the combination therapy. The CheckMate 214 study compared immunotherapy with nivolumab plus ipilimumab versus sunitinib in patients with metastatic renal cell carcinoma. There were included patients with intermediate or low-risk disease based on international carcinoma database criteria.
In metastatic renal cell, it was demonstrated that the combination therapy resulted in a significant improvement in the objective response rate, but did not reveal an improvement in progression-free survival. In the favorable risk group, sunitinib was superior compared to the combination of nivolumab and ipilimumab.
The phase 1b study JAVELIN Renal 100 is underway. This study compares avelumab plus axitinib as the first-line treatment in clear cell cell carcinoma. In addition, there are several future studies that combine pembrolizumab with other drugs, including axitinib, epacadostat and lenvatinib(33).
Immunotherapy in bladder cancer
In the past two years, the market has been flooded with five new approvals of control site inhibitors, including monoclonal antibodies that block PD-L1 (atezolizumab, durvalumab and avelumab) and PD-1 blocking monoclonal antibodies (nivolumab and pembrolizumab). With five new but relatively similar immunotherapies, the question arises: What is the best option for patients with metastatic urinary bladder cancer? Let’s take a closer look at three of the most commonly used control site inhibitors: atezolizumab, nivolumab and pembrolizumab.
Atezolizumab was first approved by the FDA in May 2016 for metastatic urothelial cancer previously treated with platinum therapy, and it was more recently approved for first-line therapy in patients who are not eligible for cisplatin.
Nivolumab was approved in February 2017 for patients with platinum-based chemotherapy based on single-arm phase II data from Checkmate-275, reporting a confirmed response rate of 19.6% complete response and 17% partial response irrespective of presence of PD-L1. Grade 3 and 4 adverse events were reported in 18% of patients, of whom the most common were fatigue and grade 3 diarrhea. Nivolumab has also been studied in association with ipilimumab in urothelial cancer, with early signs of improvement effectiveness, although the latter has not been approved at this time.
Pembrolizumab is approved for use in patients with advanced urothelial cancer who had previously platinum-based therapy, as well as in patients who are not receiving treatment and are not eligible for cisplatin. The pivotal study KEYNOTE-045, a phase III open-label study in which patients were randomly assigned to receive pemblobulzumab or chemotherapy chosen by the investigator, demonstrated a global survival benefit of pembrolizumab to chemotherapy. Patients receiving pembrolizumab demonstrated an objectively reported response rate of 21.1% compared to 11% in the chemotherapy arm. The pembrolizumab arm had a median overall survival of 10.3 months, compared with 7.4 months in the chemotherapy arm. This survival benefit was maintained at a follow-up of 18.5 months, regardless of PD-L1 expression, age, chemotherapy with investigator choice, performance status, previous therapy or histology. Similar to nivolumab, grade 3 and 4 adverse events were observed in 16.5% of patients, although immune-related adverse reactions occurred in less than 10 patients. With similar mechanical pathways, the side effect profile and rates of response, it is difficult to determine the best treatment option for each patient. However, based on current data, pembrolizumab appears to be the best option because it is the only inhibitor of the control point in urothelial carcinoma with evidence of grade 1 in a phase III clinical trial, with an overall improved survival benefit versus chemotherapy(34).
Immunotherapy in biliary tract cancer
Biliary tract diseases represent a potentially attractive target for immunotherapy, given the background association with chronic inflammation and affections such as cholecystitis, sclerosing colangitis and primary biliary cirrhosis.
Recognizing that activated tumor microclimate that exists in biliary cancers encourages the focus on adoptive therapy. Tumor antigens are identified and the presence of both CD4+, CD8+ and Fox3+ lymphocytes and macrophages suggests that the antigen response can occur in selected patients and that the relevant cells can be isolated and stimulated ex vivo. The correlation of activated immune cell infiltration and better results support a focus on this area. The types of immunotherapy experienced in biliary tract cancers:
vaccination with peptide tumor antigens that can also be loaded into dendritic cells to enhance recognition;
adoptive immunotherapy in which patient T cells are ex vivo and reinfused;
inversion of immune suppression induced by tumor cells.
Studies on both dendritic cell vaccines against both antigens (WT1, MUC-1) and a randomized chemotherapy study and WT1 vaccine in patients with advanced biliary cancer have been described.
The study by Nakamura et al.(8) found that the worst prognosis for patients with biliary tract cancer (BTC) was that of those with relatively hypermutated tumors and increased expression of control point molecules such as CTLA-4 and PDL-1. In total, 45.2% of the cases showed an increase in the expression of the immune control molecules. In Keynote-026, a study of pembrolizumab in patients with advanced biliary tract cancer, Bang et al.(33) reported intermediate outcomes: out of 89 patients who were examined, 37 (42%) had positive PD-L1 tumors, of which 24 were studied. Eight patients (34%) had a disease or stable disease of 40+ weeks.
Recently, the unpacking of the mechanisms behind tumor-induced immunosuppression has created optimism throughout the cancer community. Data on melanoma, non-small cell lung cancer and renal cancer have all sparked the search for the identification of suitable patients for PD-1, PDL-1 and CTLA4 therapies, which can reverse the immune suppression. The study by Nakamura et al. found that the worst prognosis for BTC patients was in those with relatively hypermutated tumors and elevated expression of checkpoint molecules such as CTLA-4 and PDL-1. In total, 45.2% of cases showed an increase in the expression of immune checkpoint molecules. In Keynote-026, and a trial of pembrolizumab in advanced biliary tract patients, Bang et al. reported interim results: out of 89 screened patients, 37 (42%) had PD-L1-positive tumors, of which 24 were studied. Eight patients (34%) had a response or stable disease lasting for 40+ weeks. The variability in immune predictors by the anatomic site suggests a need for appropriate selection to trials(25). In addition, there is a potential for augmenting tumor immunity with both chemotherapy and radiation. Ultimately, the combinations of studies that use all three approaches to immunotherapy in the context of standard therapy are the most likely to provide sustained benefit(35).
Immunoterapy in head and neck cancers
Half of the nasopharyngeal squamous cancers exhibit PD-L1 expression, this expression being higher in HPV-positive tumors. In recent clinical trials, a better therapeutic response to anti-PD-1 was achieved in patients with a higher PD-L1 expression. The FDA has approved the use of these drugs without mentioning the need to select the patients for PD-L1 status. The TIL activation status, density and localization, as well as PD-L2, g-interferon, inflammatory cytokines, the epithelium-mesenchymal transition phenotype, and the mutagenic burden may be all potential therapeutic response markers. For Epstein-Barr virus-induced non-keratinizing (EBV)-induced nasopharyngeal cancer, PD-L1 is overexpressed compared to EBV-negative tumors. A 22% response rate has been observed under anti-PD-1 treatment among PD-L1-positive nasopharyngeal carcinomas patients(36).
Breast cancer immunotherapy
The National Cancer Institute (NCI) published the results of research into breast cancer immunotherapy that has led to a complete disappearance of tumors in a particular case presented in a woman with metastatic advanced breast cancer.
The findings show how lymphocyte infiltration of naturally occurring tumors (TIL) has been extracted from the patient’s tumor. Lymphocytes grown on cell cultures were multiplied and injected back into the patient. The patient had previously received several treatments, including hormonal therapies and chemotherapy, but nothing has stopped cancer progression. After treatment, all of the patient’s tumors disappeared and after 22 months they did not relapse, the patient being still in remission.
In study KEYNOTE-086 of pembrolizumab (Keytruda®) in triple-negative metastatic breast cancer (TNBC), the patients were separated into two cohorts. In the A1 cohort, consisted of 170 women with previously treated disease, only one female responded completely and eight women responded partially (ORR 4.7%; CI 95%; 2.3-9.2%). For cohort B of KEYNOTE-086, pembrolizumab was administered as first-line therapy to 84 patients whose metastatic TNBC expressed PD-L1, finding an ORR of 23%.
Similar results from a monotherapy trial of atezolizumab were found, both in actual response rates and in the fact that pretreated patients were far less likely to respond than patients who had not been treated previously. In the 115 TNBC women, the overall response rate (ORR) was 10%. There have also been high levels of PD-L1 expression (defined as ≥5% positive immune infiltration cells) that have improved this figure, but the real predictor of the response appears to be the previous treatment.
However, studies combining control-site blocking with other medicinal products have found higher response rates with a combination of pembrolizumab (Keytruda®), while eribulin induced a 26.4% ORR in 106 patients with metastatic TNBC which were enrolled in the ENHANCE1/KEYNOTE-150 Ib/II trial. ORR was similar among the 65 untreated patients (29.2%; 95% CI; 18.6-41.8%) and 41 patients who received one or two previous treatments (22%; CI 95%; 10.6-37.6%). Previously treated women responded slightly better than women who had not previously received treatment. There was a total median overall survival (OS) of 17.7 months (95% CI, 13.7 – not estimable)(37,38).
Conflict of interests: The author declares no conflict of interests.