Erin M. Burns, PhD, MSPH

Approximately 20% of cancers worldwide are linked to an infectious agent. Currently, there are seven known oncogenic viruses, which include Epstein-Barr virus (EBV), hepatitis virus B and C (HBV and HCV), human papillomavirus (HPV), human T cell lymphoma virus 1 (HTLV-1), Kaposi sarcoma virus (also known as human herpes virus 8; KSVH or HHV8) and Merkel cell polyomavirus (MCPyV ). Among these agents, HBV, HCV and HPV each contribute to approximately 5% of all cancer cases.

HBV and HCV contribute to liver cancer development, and HCV can also cause non-Hodgkin lymphoma. There are at least 12 strains of HPV that can contribute to the development of anal, cervical, penile, throat, vaginal and vulvar cancer. EBV increases the risk for developing Burkitt lymphoma, Hodgkin and non-Hodgkin lymphoma, and stomach cancer. HTLV-1 has been linked with the development of adult T cell leukemia/lymphoma. HHV8 is correlated with Kaposi sarcoma in immunocompromised individuals, and MCPyV has been associated with the development of Merkel cell carcinoma.

EBV, HPV, HTLV-1, KSVH and MCPyV are classified as direct carcinogenic pathogens; a critical portion of the viral genome can be detected in each cancer cell, which leads to viral oncogene expression that disrupts cell-cycle checkpoints, inhibits apoptosis and facilitates cell immortalization. Indirect carcinogenic pathogens, including HBV and HCV, are not associated with the induction of oncogene expression. Instead, persistent infection contributes to a chronic inflammatory state that leads to the release of cytokines, chemokines, prostaglandins and reactive oxygen species, which can result in immune system dysregulation and the promotion of neovascularization.

Despite contributing to the global cancer burden, oncogenesis is an uncommon outcome of infection and is not in line with the general life cycle of these oncogenic pathogens. When it occurs, pathogen-induced oncogenesis may be observed years after the initial infection. This long time to onset demonstrates the requirement for additional steps other than infection by the pathogen alone.

Increased rates of pathogen-driven cancers have been reported in areas with increased infection rates, including underserved communities and developing countries, and in immunosuppressed populations. In a meta-analysis of patients with HIV/AIDS and transplant recipients, there was a significantly increased incidence of cancer, including EBV-related lymphoma/leukemia, HBV- and HCV-associated hepatocellular carcinoma and HPV-positive cervical cancer.

However, incidence rates of most common epithelial cancers were less than or equal to that observed in the general population. These data suggest that immunodeficiency may contribute to the observed increased cancer incidence in these populations.

&ldquo;The fundamental premise of cancer immunotherapy is that the immune system fails to identify premalignant lesions that can progress into cancer,&rdquo; explained

, director of UPMC Hillman Cancer Center, Hillman professor of oncology, associate vice chancellor for cancer research, and co-director of the Tumor Microenvironment Center in Pittsburgh. &ldquo;Viruses provide an ideal model, in a way, to understand the failure of the host immune system to control a precancerous lesion, in this case, driven by oncogenic viruses.&rdquo; Ferris co-chaired the concurrent session on virus-driven cancers during the Society for Immunotherapy of Cancer&rsquo;s 34th Annual Meeting (SITC 2019).

According to Ferris, commonalities need to be drawn regarding the similarities and differences of viruses, the identification of viral gene products capable of transforming normal cells into malignant cells and the contributions of viruses to metastasis and invasion.

&ldquo;As we&rsquo;ve come to learn, one of the key features of viruses that can cause cancer is the ability to downregulate or escape the normal immune system response, permitting them to grow unchecked while they turn their target cell into a precancerous lesion,&rdquo; said Ferris. &ldquo;We have tried to identify ways to incorporate novel, innovative diagnostic or therapeutic strategies and combinations to reactivateand I think that&rsquo;s one of the keys&mdash;the antiviral immunity as a mechanism of treatment.&rdquo;

During his training, Ferris was involved in work on cancer vaccines against HPV, working at Johns Hopkins University where investigators initially made the observation that HPV was present in head and neck cancers. &ldquo;That was sort of what got me very interested in immunotherapy of head and neck cancers because you had a target; something to shoot at,&rdquo; explained Ferris.

In a two-year update of long-term survival of patients treated with nivolumab (Opdivo) or investigator&rsquo;s choice for recurrent or metastatic squamous cell carcinoma of the head and neck, the 24-month overall survival rate was nearly three times higher with nivolumab therapy than it was with investigator&rsquo;s choice, regardless of tumor HPV status. Studies are ongoing to investigate the combination of HPV-targeted immunotherapy and anti-PD-1 in head and neck cancer.

Traditionally, head and neck cancer development is associated with excessive tobacco and alcohol use.

Patients with HPV-positive cancers tend to have better outcomes. &ldquo;It&rsquo;s unfortunate that these folks contract these cancers, but I should point out that HPV in head and neck cancer has a dramatically better prognosis than HPV-negative cancer,&rdquo; explained Ferris. Areas of future investigation include determining why HPV-positive head and neck cancer patients have approximately twice the survival of patients with HPV-negative tumors.

It is important to remember that not all virus-induced cancers arise or are at an increased frequency in situations of immunosuppression. However, this is the case for Merkel cell carcinomas. The factors that contribute to Merkel cell carcinoma development are not fully understood, but the incidence of Merkel cell carcinoma is higher in immunosuppressed and elderly individuals than it is in immunocompetent and younger individuals.

Merkel cell carcinoma develops when Merkel cells, which are found in the epidermis near nerve endings, grow out of control (

). It is a rare neuroendocrine tumor that had an estimated incidence rate of 0.18 to 0.41 per 100,000 population in 2006. However, over the last 20 years the incidence rate of Merkel cell carcinoma has increased to approximately 0.7 cases per 100,000 person-years in the United States in 2013. This increase has been attributed to improved diagnostic tools and an increasingly aged population based on the exponentially increasing incidence of Merkel cell carcinoma with age.

Risk factors include high levels of natural and artificial sunlight exposure, a history of other cancer diagnoses, age greater than 50 years, male sex, white race and having a weakened immune system due to disease or immunosuppressive drugs (such as after organ transplantation).

Approximately 10% of patients with Merkel cell carcinoma have chronic immunosuppression, which is a greater rate than that seen in the general population. Furthermore, patients with immuno-suppressed Merkel cell carcinoma have significantly reduced cancer-specific survival rates than patients with non-immunosuppressed Merkel cell carcinoma (40% versus 74% at three years, respectively). These data suggest that immuno-suppressed patients have an increased likelihood of developing Merkel cell carcinoma and they are more likely to die from the disease, which high- lights the importance of immune regulation in this virus-driven cancer.

&ldquo;Until very recently, we did not have any effective therapies that could prolong life for people whose Merkel cell cancer had spread to the point where it could not be removed surgically,&rdquo; explained Suzanne L. Topalian, MD, Bloomberg-Kimmel professor of cancer immunotherapy, professor of surgery and oncology at Johns Hopkins University School of Medicine, director of the melanoma program at the Kimmel Cancer Center and associate director of the Bloomberg-Kimmel Institute for Cancer Immunotherapy, all in Baltimore, Md.

&ldquo;Those patients were typically treated with combination chemotherapy or radiation therapy, but their prognosis was still very limited, with life expectancy, on average, less than a year after the diagnosis of advanced metastatic Merkel cell carcinoma,&rdquo; said Topalian, who presented during this concurrent session. &ldquo;A real revolution in how we treat Merkel cell cancer came when antiPD-1 and PD-L1 drugs were tested against this disease.&rdquo;

In 2016, in a phase 2 study of 26 patients with advanced Merkel cell carcinoma who had not received previous systemic therapy and were treated with pembrolizumab (Keytruda), the objective response rate (ORR) was 56% among 25 patients with one or more evaluations.16 Among these patients, four had a complete response and 10 had a partial response. Over a median follow-up of 33 weeks, two of the 14 patients who had a response experienced relapse, with a response duration ranging from 2.2 months to 9.7 months. The six-month progression-free survival rate was 67%. Among the 16 patients with MCPyV-positive tumors, the response rate was 62%, whereas it was 44% among those with virus-negative tumors.

In a multicenter, open-label, phase 2 study, 88 patients with stage IV chemotherapy-refractory, histologically confirmed Merkel cell carcinoma were treated with at least one dose of avelumab (Bavencio)).

After a median follow-up of 10.4 months, 32% of patients achieved an objective response, including eight complete responses and 20 partial responses. At the time of analysis, 82% of responses were ongoing (

&ldquo;Both of those trials showed substantial response rates to these drugs, and they indicated in early results that the responses appeared to be durable,&rdquo; noted Topalian. These studies have recently reported long-term follow-up data, confirming the durability of many responses.

Of 50 patients treated with pembrolizumab for up to two years, the ORR was 56%, with an ORR of 59% in virus-positive tumors and an ORR of 53% in virus-negative tumors. The 24-month progression-free and overall survival rates were 48.3% and 68.7%, respectively. Treatment-related adverse events of grade 3 or higher were reported in 28% of patients, leading to discontinuation of treatment in 14% of patients, with one patient death.

Among 88 patients treated with avelumab and followed for at least 12 months, there was a confirmed ORR of 33%, including 11% complete responses. Approximately 74% of responses lasted at least one year, with 72.4% of responses ongoing at the time of analysis. The median duration of response was not reached. The one-year progression-free and overall survival rates were 30% and 52%, respectively. Durable responses were reported irrespective of MCPyV status.

&ldquo;This is really great news for patients with this disease, but what we learned scientifically, and what we published in 2016, was that responses to antiPD-1 treatment were similar in the two major groups of Merkel cell cancers, which are those cancers that are caused by the Merkel cell polyomavirus and those that are not,&rdquo; explained Topalian.

A study designed to evaluate the genetic basis of Merkel cell carcinoma via exome sequencing reported that MCPyV-negative tumors had a high mutation burden, with a median of 1,121 somatic single nucleotide variants (SSNVs) per tumor, whereas MCPyV-positive tumors had a low mutation burden, with a median of 12.5 SSNVs per tumor. Additionally, MCPyV-negative Merkel cell carcinomas harbored more predicted tumor neoantigens than melanomas or non-small cell lung cancers, for which immune checkpoint blockade has been shown to lead to durable clinical responses. These data suggest that these tumors would be good targets for immunotherapy because the high expression of neoantigens should lead to stronger immune responses and tumor rejection.

&ldquo;I would say that Merkel cell cancers that are virus-positive really break that mold because they don&rsquo;t have lot of mutations,&rdquo; said Topalian. &ldquo;But what they do have are viral proteins, which are very strong immunogens. This cancer teaches us that it&rsquo;s not only the number of tumor antigens that is important for cancer rejection, it&rsquo;s the quality of those antigens, and how strong they are, in terms of how highly they provoke an immune response.&rdquo;

Current studies in Merkel cell carcinoma are focused on improving the results that have been reported with antiPD-1 and anti&ndash;PD-L1 therapy. Biomarkers are needed to help identify the patients that are most likely to respond or not respond to therapy. Additionally, studies are needed to elucidate the mechanisms contributing to treatment resistance in order to develop more powerful combination therapies.

Additional studies are underway using immunotherapy to treat patients with Merkel cell carcinoma at earlier stages with adjuvant or neoadjuvant therapy. &ldquo;We reported some preliminary results with the antiPD-1 drug, nivolumab, in the neoadjuvant setting at ASCO [American Society of Clinical Oncology] 2018,&rdquo; explained Topalian. &ldquo;We saw a high rate of pathologic responses in the resected tumor specimens and we found that result very promising, so now there are other trials ongoing to look at neoadjuvant forms of immunotherapy in Merkel cell cancer.&rdquo;

PD-L1 and microsatellite instability (MSI), which is associated with a very high tumor mutational burden, are two biomarkers that are FDA-approved for directing antiPD-1 or anti&ndash; PD-L1 therapy in certain cancer types. However, in Merkel cell carcinoma, a high mutation burden will not inform selection of patients for therapy because there are high response rates in virus-positive tumors, which have a low tumor mutational burden, and in virus-negative tumors, which have a high tumor mutational burden.

&ldquo;We have also published that the PD-L1 marker doesn&rsquo;t seem to help us here,&rdquo; explained Topalian. &ldquo;In our studies of pembrolizumab treatment in the advanced disease setting, PD-L1 expression in pre-treatment tumor biopsies did not correlate with response, so that really means that we need to look at some different markers for Merkel cell cancer. That is a very active area of research.&rdquo;

According to Topalian, three things to note about Merkel cell carcinoma and virus-induced cancers are that viral antigens can act as tumor rejection antigens, a high tumor mutational burden is not required for response to antiPD-1 therapies, and applying immunotherapy in earlier disease settings may be advantageous.

&ldquo;By understanding viruses, it provides a model not only to treat the virus-induced cancers that affect 20% percent of the population, but also it may give us a molecular window into how even non-virus-induced cancers may get triggered,&rdquo; explained Ferris.

According to Ferris, nonvirus-induced cancers may be able to mutate through the same pathways as viruses, but through genomic alterations. Viruses provide a molecular window into how a cell becomes cancerous. &ldquo;They&rsquo;ve been selected for hundreds and thousands of years for these kinds of things, so researchers can learn a lot by understanding this subsetthis minority of the world&rsquo;s cancers&mdash;that may be applicable to others,&rdquo; concluded Ferris.

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Nghiem PT, Bhatia S, Lipson EJ, et al. PD-1 blockade with pembrolizumab in advanced Merkel-cell carcinoma.

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Kaufman HL, Russell J, Hamid O, et al. Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial.

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Nghiem P, Bhatia S, Lipson EJ, et al. Durable tumor regression and overall survival in patients with advanced Merkel cell carcinoma receiving pembrolizumab as first-line therapy.

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Articles

Approximately 20% of cancers worldwide are linked to an infectious agent. Currently, there are seven known oncogenic viruses, which include Epstein-Barr virus, hepatitis virus B and C, human papillomavirus, human T cell lymphoma virus 1, Kaposi sarcoma virus and Merkel cell polyomavirus. Among these agents, HBV, HCV and HPV each contribute to ap- proximately 5% of all cancer cases.

Understanding Virus-Induced Cancers Can Elucidate Precancerous Lesion Development

ombinations approved this year and more under investigation, optimizing therapy selection for each patient&rsquo;s unique disease characteristics and needs is becoming increasingly important.

Worldwide, incidence of renal cell carcinoma (RCC) is increasing. In the United States, there were 73,820 estimated new cases in 2019.1 Cytotoxic chemotherapy has shown limited efficacy in metastatic RCC, but immunotherapeutic and antiangiogenic approaches have introduced promising treatment modalities.

The use of immunotherapy has made a significant impact on the treatment of patients with RCC, first with single agents and then with combination regimens.

&ldquo;Immunotherapy is now considered largely [a] standard of care,&rdquo; explained

. &ldquo;There are 3 combinational regimens approved for the first line in kidney cancer.&rdquo;

Cho, an associate professor in the Department of Medicine and director of the Phase I Drug Development Program at NYU Langone Health in New York, New York, will speak during his presentation, &ldquo;Next-Generation Immunotherapy in Renal Cell Carcinoma,&rdquo; as part of the Genitourinary Cancer track during the afternoon session of today&rsquo;s meeting.

First- and second-line therapeutic options for patients with RCC include targeted therapy using tyrosine kinase inhibitors (TKIs) and/ or antivascular endothelial growth factor antibodies. Additional agents targeting the mammalian target of rapamycin are also options in this setting. FDA-approved agents for advanced RCC treatment in the first line and/or subsequent lines of therapy include sunitinib (Sutent), sorafenib (Nexavar), pazopanib (Votrient), axitinib (Inlyta), temsirolimus (Torisel), everolimus (Afinitor), bevacizumab (Avastin) in combination with interferon, cabozantinib (Cabometyx), and lenvatinib (Lenvima) plus everolimus.

The current National Comprehensive Cancer Network Guidelines outline preferred and other recommendations for patients with clear cell RCC, and these include combinations of PD-1 inhibitors with axitinib and inhibitors of CTLA-4 and PD-1 (

The combination of ipilimumab (Yervoy) and nivolumab (Opdivo) was approved by the FDA for use in the frontline setting in April 2018 based on findings from the phase III CheckMate 214 trial.

In this trial, 1096 patients with previously untreated clear cell advanced RCC were randomized to nivolumab (3 mg/kg body weight) plus ipilimumab (1 mg/kg) every 3 weeks for 4 doses, followed by nivolumab every 2 weeks or sunitinib (50 mg) once daily for 4 weeks.

After a median follow-up of 25 months, the 18-month overall survival (OS) rate was 75% with nivolumab plus ipilimumab and 60% with sunitinib.

Median progression-free survival (PFS) was also significantly prolonged with ipilimumab plus nivolumab. The objective response rate (ORR) was significantly higher with the combination compared with sunitinib (42% vs 27%), with complete response (CR) rates of 9% and 1%, respectively. Grade 3/4 adverse events (AEs) occurred in 46% of patients treated with ipilimumab plus nivolumab and 63% of patients treated with sunitinib.

&ldquo;This trial showed an efficacy and OS benefit of nivolumab plus ipilimumab over sunitinib in the first-line treatment of intermediate- or poor-risk advanced clear cell RCC,&rdquo; noted Robert J. Motzer, MD, kidney cancer section head of the Genitourinary Oncology Service and the Jack and Dorothy Byrne Chair in Clinical Oncology, at Memorial Sloan Kettering Cancer Center in New York, New York, and colleagues in the

.6 Motzer will also be speaking today during the session, &ldquo;First-Line Metastatic Renal Cell Carcinoma: What Is the Right Choice?&rdquo;

Axitinib in combination with pembrolizumab (Keytruda) was approved by the FDA in April 2019 for the first-line treatment of patients with advanced RCC, a decision that was supported by data from the phase III KEYNOTE-426 trial.

In this trial, 861 patients with previously untreated advanced clear cell RCC were randomized to receive pembrolizumab (200 mg) once every 3 weeks plus axitinib (5 mg) twice daily or sunitinib (50 mg) once daily for the first 4 weeks of each 6-week cycle. At 12 months, the estimated percentage of patients remaining alive was significantly higher in the pembrolizumab/axitinib group compared with the sunitinib group (89.9% vs 78.3%;

<.0001). The median PFS (15.1 vs 11.1 months) and ORR (59.3% vs 35.7%) both increased in patients treated with pembrolizumab/axitinib compared with sunitinib.

Importantly, the benefit of the combination regimen was observed in patients with favorable-, intermediate-, and poor-risk disease, regardless of PD-L1 expression. Similar rates of grade &ge;3 AEs were reported in both groups.

&ldquo;TKIs and checkpoint blockers like avelumab [Bavencio] both may have potential immune-modulating functions that, when combined, may provide clinical benefit in patients with advanced RCC that exceeds the effects of the respective drugs alone, without compromising toxicity,&rdquo; Motzer noted in a press release.

The combination of avelumab plus axitinib was also approved this year in May for the frontline treatment of patients with advanced RCC based on results from the phase III JAVELIN Renal 101 trial.

In this study, 886 patients with previously untreated advanced RCC were randomized to receive avelumab (10 mg/kg) every 2 weeks plus axitinib (5 mg) twice daily or sunitinib (50 mg) once daily for 4 weeks. Compared with patients treated with sunitinib, those treated with avelumab/axitinib had a greater median PFS overall (13.8 vs 8.4 months;

<.001) and among the 560 patients with PD-L1positive tumors (13.8 months vs 7.2 months;

<.001). The ORR was significantly higher in patients with PD-L1positive tumors treated with the combination compared with sunitinib (55.2% vs 25.5%). AEs were reported in most patients in both groups, with grade &ge;3 AEs in 71.2% of patients treated with avelumab/axitinib and 71.5% treated with sunitinib.

&ldquo;JAVELIN Renal 101 is the first positive phase III study combining an immune checkpoint blocker with a TKI compared with TKI alone in the first-line treatment of advanced RCC,&rdquo; Motzer noted in a press release. &ldquo;The findings support the potential of avelumab plus axitinib as a new treatment approach for patients with advanced RCC. The combination benefit was shown in all subgroups of patients, by independent review as well as by investigators, and whether tumor cells stained positive for PD-L1 or not,&rdquo; he explained.

When it comes to deciding which therapy to choose for individual patients, Cho explained that it depends on the urgency with which you need a response. &ldquo;I think one of the shortcomings of immunotherapy is that the response kinetics are unpredictable, meaning we don&rsquo;t know how quickly patients will respond,&rdquo; he said. He also noted that for some patients, tumors may grow before any tumor growth inhibition effects are seen, which suggests that immunotherapy may not be the best choice for patients with a large tumor burden or quickly growing cancer or for those who are symptomatic.

&ldquo;The way I choose between them is I make an assessment for how quickly I need that patient to respond,&rdquo; Cho said. &ldquo;If they need to respond quickly, I prefer to use a TKI-based regimen, which [includes] 1 of the 2 combinations of axitinib and either pembrolizumab or avelumab, mainly because I feel that the response with the TKI is just much more reliable in terms of onset of response.&rdquo;

There are other combinations of TKI and PD-1 agents under investigation, including cabozantinib with nivolumab, lenvatinib with pembrolizumab, and bevacizumab plus atezolizumab, which have already been studied. &ldquo;They are similar to the existing combinations that are available, so it&rsquo;s going to be a matter of physician preference as to which of those combinations you use,&rdquo; explained Cho.

In addition to the many FDA-approved regimens for use in this patient population, emerging immunotherapy combinations have potential to contribute to future change in the treatment paradigm of RCC.

Results from a phase I/II trial designed to evaluate the safety and efficacy of pembrolizumab plus cabozantinib in 8 patients with metastatic RCC were reported at the 2019 Genitourinary Cancers Symposium. No dose-limiting toxicities were reported with grade 1/2 drug-related AEs that included fatigue, weight loss, anorexia, diarrhea, dysgeusia, and abnormal liver function tests. A single case of grade 3 reversible posterior leukoencephalopathy syndrome attributed to cabozantinib was reported. No patients receiving cabozantinib at 40 mg required dose reductions; 1 patient at 60 mg did. The clinical benefit rate was 87.5%, including 2 partial responses (PRs) and 5 patients with stable disease. No correlation was seen between response and PD-L1 status. Based on these encouraging preliminary efficacy results, the dose-expansion phase of the phase II trial is currently enrolling patients.

Promising antitumor activity has also been reported with first-line, single-agent pembrolizumab in key patient subgroups with clear cell RCC in cohort A of KEYNOTE-427 and was reported at the 2018 American Society of Clinical Oncology Annual Meeting. In patients with International Metastatic Renal Cell Carcinoma Database Consortium favorable risk, the ORR was 32%.

Cohort B of KEYNOTE-427, which was reported at this year&rsquo;s Genitourinary Cancers Symposium, included 165 patients with non clear cell RCC treated with pembrolizumab monotherapy. The ORR was 24.8%, consisting of 8 CRs and 33 PRs. Overall, 55.2% of patients experienced a reduction in tumor burden, including 4.2% who experienced 100% tumor burden reduction. The median PFS was 4.1 months, and the median OS was not reached. Overall, 64% of patients reported treatment-related AEs, including grade &ge;3 colitis, hepatitis, fatigue, and type 1 diabetes.

Discontinuation due to treatment-related AEs was reported in 6% of patients. The safety profile was generally as expected, based on reports in other tumor types. These results support continued investigation of single-agent pembrolizumab in this patient population.

Nivolumab and tivozanib, a vascular endothelial growth factor receptor TKI, was investigated in the phase II portion of a dose-escalation and -expansion trial involving 25 patients with metastatic RCC and was recently reported at the European Society for Medical Oncology 2019 Congress. Among these, 8 patients had favorable-risk disease, 19 had intermediate-risk disease, and 1 had poor-risk disease; clear cell histology was reported in 22 patients. For previously untreated patients, the median PFS was 18.5 months. The median was not reached in previously treated patients. The disease control rate was 96%, and the ORR was 56%, including 1 CR and 1 unconfirmed PR. The most frequently reported treatment-related grade 3/4 AE was hypertension (44%). According to the authors, this combination compares well with other combinations of TKIs and immunotherapy, warranting additional studies.

Ilixadencel, an off-the-shelf cancer immune primer developed for the treatment of solid tumors, has also been investigated in combination with sunitinib in patients with newly diagnosed intermediate- and poor-risk metastatic RCC.

The agent is a cell-based product that consists of pro-inflammatory allogeneic dendritic cells that secrete high amounts of proinflammatory cytokines and chemokines when administered intratumorally.

In an open-label, phase II study, 88 patients were treated with 2 intratumoral doses of ilixadencel before nephrectomy and subsequent treatment with sunitinib or sunitinib therapy alone post nephrectomy. Among 70 evaluable patients, complete tumor responses were observed in 11% who received ilixadencel compared with 4% who received sunitinib alone. The corresponding 18-month survival rates were similar in both groups (63% vs 66%).

Safety and tolerability were also similar in both groups, and they were consistent with previously reported safety data for ilixadencel.

&ldquo;There&rsquo;s another drug in assessment, NKTR-214, which is a pegylated version of interleukin [IL]-2, which is being studied in a phase III trial in combination with nivolumab [NCT03729245],&rdquo; Cho said. &ldquo;That is also a pure immunotherapy, unlike the TKI combinations, so that is something that has the chance of potentially shifting things if the efficacy data are promising.&rdquo;

When thinking about unanswered questions regarding the treatment of RCC, it is important to consider ways to improve the quality of response, which is measured in patients who are complete responders or in those who have durable CRs. &ldquo;The biggest question is, can we cure more patients with kidney cancer and how do we do that,&rdquo; explained Cho. &ldquo;I think the novel immunotherapies are the only way to get there because we know from our past experience with high-dose IL-2 that we can actually cure patients with kidney cancer using immunotherapy.&rdquo;

Another important concern is identifying therapies to use in the second line following the use of the most effective drugs in combination in the first line. &ldquo;We are going to be seeing a lot of that with patients who get a combination of a TKI plus a PD-1 [inhibitor] in the frontline,&rdquo; Cho said. &ldquo;I think what happens in the second line is going to become a much more interesting situation.&rdquo;

Overall, it is important to remember that RCC is curable, which should be the ultimate goal. &ldquo;We shouldn&rsquo;t be too consumed with increasing response rates and other metrics of response,&rdquo; noted Cho. &ldquo;I think we need to be focused on what is the most important thing, which is curing patients with kidney cancer.&rdquo;

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FDA approves pembrolizumab plus axitinib for advanced renal cell carcinoma. FDA website. fda.gov/drugs/drug-approvals-and- databases/fda-approves-pembrolizumab-plus-axitinib-advanced- renal-cell-carcinoma. Published April 19, 2019. Accessed October 15, 2019.

Rini BI, Plimack ER, Stus V, et al; Keynote-426 Investigators. Pembrolizumab plus axitinib versus sunitinib for advanced renal cell carcinoma.

. 2019;380(12):1116-1127. doi: 10.1056/ NEJMoa1816714.

FDA approves Bavencio (Avelumab) plus Inlyta (Axitinib) combination for patients with advanced renal cell carcinoma [news release]. Darmstadt, Germany: Pfizer Oncology; May 14, 2019. pfizer.com/news/press-release/press-release-detail/fda_approves_ bavencio_avelumab_plus_inlyta_axitinib_combination_for_patients_ with_advanced_renal_cell_carcinoma. Accessed October 14, 2019.

Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma.

. 2019;380(12):1103-1115. doi: 10.1056/NEJMoa1816047.

Keeler ME, Kessler ER, Bernard B, et al. Pembrolizumab (pembro) and cabozantinib (cabo) in patients (pts) with metastatic renal cell carcinoma (mRCC): Phase I results.

. 2019;37(suppl 7;abstr 600). doi: 10.1200/JCO.2019.37.7_suppl.600.

McDermott DF, Lee JL, Szczylik C, et al. Pembrolizumab monotherapy as first-line therapy in advanced clear cell renal cell carcinoma (accRCC): Results from cohort A of KEYNOTE- 427.

. 2018;36(suppl 15;abstr 4500). doi: 10.1200/ JCO.2018.36.15_suppl.4500.

McDermott DF, Lee JL, Ziobro M, et al. First-line pembrolizumab monotherapy for advanced non-clear cell renal cell carcinoma: results from KEYNOTE-427 cohort B.

. 2019;37(suppl 7;abstr 546). doi: 10.1200/JCO.2019.37.7_suppl.546.

Barthelemy P, Escudier B, Negrier S, Ravaud A, Needle MN, Albiges L. TiNivo: Tivozanib combined with nivolumab results in prolonged progression free survival in patients with metastatic renal cell carcinoma (mRCC).

. 2019;30(suppl 5;abstr 947P). doi: 10.1093/annonc/mdz249.043.

Immunicum AB (publ) announces positive phase II MERECA topline results including complete tumor responses in metastatic renal cell carcinoma patients [news release]. Stockholm, Sweden: Immunicum AB; August 29, 2019. immunicum.se/investors/press-releases/press/?xml_id=1908171. Accessed October 15, 2019.

Karlsson-Parra A, Kovacka J, Heimann E, et al. Ilixadencel  an allogeneic cell-based anticancer immune primer for intratumoral administration.

. 2018;35(8):156. doi: 10.1007/ s11095-018-2438-x.

Cytotoxic chemotherapy has shown limited efficacy in metastatic RCC, but immunotherapeutic and antiangiogenic approaches have introduced promising treatment modalities. The use of immunotherapy has made a significant impact on the treatment of patients with RCC, first with single agents and then with combination regimens.

Choosing Frontline Regimens in Different RCC Patient Populations and Future Promise  of Novel Therapies

Over the last decade, immunotherapeutic options have led to impressive clinical responses in patients with various cancer types and this has increased expectations for successful treatment of the disease. Despite immunotherapy results leading to clinical trials in melanoma, renal cell carcinoma and nonsmall cell lung cancer, the percentage of patients who respond to immunotherapy remains low; this highlights the need to identify the patient population that will best respond to these approaches.

One of the main immunotherapeutic strategies is immune checkpoint blockade, the inhibition of the immune system&rsquo;s intrinsic regulatory mechanisms to drive the activation of an improved anti-cancer immunological response.1 An improved understanding of the mechanisms that cancer cells use to hide from the immune system has contributed to the development of new approaches against cancer. Particular success has been reported following treatment with inhibitors against the immune checkpoint proteins cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1). CTLA-4 is a membrane receptor found on effector T cells that binds cluster of differentiation (CD)80/CD86 on antigen-presenting cells, which leads to T cell arrest.2 PD-1 is also a cell membrane receptor of activated T cells, and it interacts with its ligands, PD-L1 and PD-L2, to induce T-cell inhibition.

Because only a fraction of patients experience effective responses to these immune checkpoint inhibitors, new approaches targeting additional immune-regulating mechanisms or combinations of existing agents are under investigation.

&ldquo;Like many people, I&rsquo;m very interested in learning what are any updates on new immune modulators that are, first of all, being evaluated in the preclinical space and also those that are beginning human clinical trials,&rdquo; explained

, the Lloyd J. Old/Virginia and Daniel K Ludwig chair in clinical investigation, chief of immuno-oncology service, director of the Parker Institute for Cancer Immunotherapy, and associate director of the Ludwig Center for Cancer Immunotherapy at Memorial Sloan Kettering Cancer Center in New York.

&ldquo;The major unanswered questions we have are what additional pathways should be explored in a rational, mechanism-based way to add to the activity of CTLA-4 and PD-1?&rdquo; Wolchok, co-chair of the &ldquo;Immune Checkpoints: Newer Targets and Update on Combinations&rdquo; session at the 34th Annual Meeting & Pre-Conference Programs of the Society for Immunotherapy of Cancer (SITC 2019), explained.

Wolchok anticipates discussions on topics surrounding the early activity of newer-generation immune modulators, including the presence of efficacy signals and whether new toxicities are observed. &ldquo;In addition, what are potential biomarkers that we might use to enhance development of these medicines and others so that they are introduced to the patient population that might benefit the most?&rdquo; said Wolchok.

Targeting CD38 to Optimize Immune Checkpoint Blockade Immunotherapy

&ldquo;In lung cancer, as in multiple other tumor types, immunotherapy obviously has made a big difference in what we do and how well patients do,&rdquo; explained

, an associate professor at The University of Texas MD Anderson Cancer Center. According to Gibbons, there are patients who experience long-term responses with immune checkpoint therapies, including CTLA-4 or PD-1 inhibitors, and there is a subset of patients who either do not have any response or have a response that is not durable there is clear evidence that resistance develops.

Results from animal models of lung cancer suggest that CD38 expression on tumor cells may play a dominant role in the development of resistance to single-agent immune checkpoint therapy. &ldquo;And this caught us by surprise because I had never heard of CD38 before, really, and didn&rsquo;t know anything about it,&rdquo; said Gibbons, who is presenting &ldquo;Targeting CD38 to Optimize PD-1/PD-L1 and CTLA-4 Blockade Immunotherapy&rdquo; on Friday, Nov. 8, at 2:05 p.m. as part of Session 204 in the Potomac Ballroom.

CD38 is normally expressed on the surface of immune cells and nonhematopoietic cells. CD38 is an ectozyme and functions to convert NAD+ to ADP-ribose (ADPR) and cADPR, which are required for regulating extracellular metabolites, cell adhesion, intracellular Ca+2, and signal transduction pathways.

Although CD38 has been shown to have activity in many immune cell types and functions that vary during development, activation and differentiation of lymphocytes, the potential function of CD38 on tumor cells is not well described.

In 2018, Gibbons and colleagues used established nonsmall cell lung cancer and melanoma tumor models to investigate immunotherapy resistance.9 They reported that tumors treated with antibodies against PD-1/PD-L1 develop resistance by means of CD38 upregulation, which is induced by all-trans retinoic acid and interferon (IFN)-&beta;. Results from in vitro and in vivo studies demonstrate that CD38 inhibits CD8+ T cell function by means of adenosine receptor signaling. Additionally, they suggested that CD38 or adenosine receptor blockade may be effective strategies to overcome resistance. Analysis of large patient tumor data sets revealed CD38 expression in a subset of tumors with high levels of basal or treatment-induced T cell infiltration into the interior of the tumor, which is where immune checkpoint therapies are thought to have the greatest effect. In animal models, combination treatment with CD38 and PD-L1 inhibitors led to therapeutic benefit. These results suggest that a combination strategy may be beneficial for many patients in whom PD-1/PD-L1 blockade is currently indicated.

&ldquo;At least part of the mechanism of what appears to be going on is that the enzymatic activity of CD38, because it acts upstream of CD73, is driving adenosine formation in the tumor microenvironment,&rdquo; explained Gibbons, &ldquo;and adenosine can be profoundly immunosuppressive.&rdquo;

Since that 2018 publication, Gibbons and col leagues have been investigating combination checkpoint therapy. Treatment with combination immune checkpoint therapy that blocks both the PD-1 and CTLA-4 axes led to pronounced upregulation of CD38. There seems to be some level of effect from the adenosine mechanism; however, there is also a differential response to single-agent CD38 blockade. &ldquo;There&rsquo;s a much better response to single-agent CD38 blockade after the resistance to combination than resistance to the single agent, suggesting that there&rsquo;s something totally different about the immune microenvironment in those tumors, even though they&rsquo;re also resistant,&rdquo; noted Gibbons.

Gibbons and his colleagues think they have found a mechanism by which CD38 is marking a subset of monocytes, normally present in tumors, that should become mature dendritic cells and will act as strong antigen-presenting cells for CD4+ and CD8+ T cells. This will drive a robust anti-tumor response. However, when CD38 expression is very high, both the immunosupeffect of adenosine as well as a lack of dendritic cell maturation result in resistance that develops over time.

&ldquo;There are many more ways that tumors acquire resistance to immune therapies than what we currently know,&rdquo; said Gibbons. &ldquo;Obviously, this is an important area for continued exploration in lung cancer but also in many other cancer types.&rdquo;

Interleukin (IL)-2 combination therapies are also under investigation. An advantage of IL-2 therapies is that they have the ability to integrate into most other forms of immune or nonimmune therapy.

Therefore, IL-2 therapy may contribute to improved responses in any situation in which T or natural killer (NK) cells are involved in the mediation of immune responses. There is suggested value for combination therapy with immune checkpoint therapy because of their distinct mechanisms of action. Preclinical and clinical studies have demonstrated synergy of both IL-2- and IL-15-based therapies with monoclonal antibodies against PD-1 and CTLA-4.

The first clinical trial designed to investigate this combination included 36 patients with metastatic melanoma who were treated with ipilimumab (Yervoy) and high-dose IL-2, and resulted in three complete responses during the initial trial period and six during follow-up.15,16 These findings provided support to the investigation of additional combinations involving IL-15/IL-15R&alpha; complex- es, pegylated IL-2, and high- and low-dose IL-2 with anti-PD-1 antibodies pembrolizumab (Keytruda) and nivolumab (Opdivo) and the anti-PD-L1 monoclonal antibody atezolizumab (Tecentriq).

A case series of nine patients with metastatic melanoma who had progressive disease while receiving monotherapy with a PD-1 inhibitor were treated with intra-tumoral IL-2 in addition to PD-1 inhibitor therapy at the time of progressive disease.

Of these, three patients had complete responses, three patients had partial responses, and three patients had progressive disease. These data support the use of additional intralesional IL-2 therapy in patients with initial resistance to PD-1 inhibitor therapy and injectable lesions.

In patients who have immunologically &ldquo;cold&rdquo; tumors, activation of tumor-resident innate immune cells may be needed to prime an adaptive immune response to promote the efficacy of immune checkpoint blockade. Toll-like receptor ( TLR) agonists function to initiate immune activation within the tumor microenvironment and to break immunosuppression and tolerance (

TLR7 and TLR9 primarily are expressed by NK cells, B cells, macrophages and plasmacytoid dendritic cells. TLR7 and TLR9 are thought to target stromal cells but not tumor cells.

Because TLR agonists act on innate immune cells, whereas PD-1 blockade targets adaptive immune cells, it has been hypothesized that antigen-presenting cell activation in the tumor microenvironment through intratumoral injection of TLR agonists may improve the efficacy of the PD-1 blockade.

In a study of mouse models of head and neck squamous cell carcinoma, intratumoral treatment with 1V270 (a TLR7 agonist) or SD-101 (a TLR9 agonist), in combination with an anti-PD-1 antibody led to suppression of tumor growth at the injected site and at distant body sites.

TLR7 agonist treatment led to an increased M1/M2 tumor-associated macrophage ratio and recruitment of activated CD8+ T cells. Combination therapy with the TLR7 agonist in conjunction with anti-PD-1 was shown to increase CD8+ T cell clonality locally and systemically. These data demonstrate a potential therapeutic mechanism for improving PD-1 blockade efficacy in head and neck squamous cell carcinoma.

The TLR7/8 agonist, MEDI9197, has been shown to activate human immune cells resulting in the secretion of IFN-&alpha;, IL-12,

and IFN-&gamma;. It should be noted that other agonists, for TLR9 and STING, only induce the release of IFN-&alpha;. When considered together, the combination of all three agonists provides a broader cytokine profile that may enhance CD8+ T cell responses. Furthermore, MEDI9197 led to tumor growth inhibition in syngeneic models. When combined with T cell-targeted immunotherapies in preclinical models, the anti-tumor activity of MEDI9197 was enhanced.

T Cell Immunoglobulin and Mucin-Domain Containing Protein-3

T cell immunoglobulin and mucin-domain containing protein-3 ( TIM-3) is constitutively activated on innate immune cells; however, the expression of TIM-3 on T cells has been associated with activated and terminally differentiated states.

Phospha- tidylserine, galectin-9, carcinoembryonic antigen-related cell adhesion molecules (CEACAM)-1 and high-mobility group box 1 (HMGB1) are proposed ligands of TIM-3.

Studies have shown that the cytoplasmic domain of TIM-3 is able to mediate intracellular signaling in myeloid cells and in T cells despite a lack of classical inhibitory or activating signaling molecules. The association of human leukocyte antigen (HLA)-B-associated transcript 3 with the cytoplasmic domain of TIM-3 has been shown to prevent T cell exhaustion and dysfunction.

Unlike PD-1 and CTLA-4, there are no reports of antigen-presenting cell-expressed membrane-bound ligands for TIM-3. In a study of breast cancer samples, TIM-3-positive cells were of myeloid origin, which implies that therapeutic approaches that target TIM-3 may strongly impact dendritic cells, macrophages and other antigen-presenting cells.

Distinct premalignant lesions with unique genetic aberrations can result from cell injury, and a subset of these lesions may escape immune surveillance and develop into invasive cancer. To date, the mutational landscape that may facilitate the prediction of progression is not well understood. To more effectively develop preventive and interception strategies, improved understanding of tumorigenesis, premalignant lesion composition, and the associated microenvironment is needed.

Kostyantyn Krysan, PhD, et al, assessed lymphocyte infiltration in premalignant lesions to identify somatic mutations. This resulted in the identification of sequenced exomes from 89 premalignant atypical adenomatous hyperplasia lesions.2

The presence of an adaptive immune response was suggested by the high presence of CD8+ and CD4+ T cells. The predicted neoantigens resulting from these mutations were highly correlated with CD8+ and CD4+ T cell infiltration and PD-L1 upregulation in premalignant lesions. Based on unique patterns of somatic mutations and neoantigens for each patient, these data demonstrate evidence of mutational heterogeneity, pathway dysregulation and immune recognition in adenomatous premalignancy.

The Future of Immune Checkpoint Inhibitor Therapy

To date, immune checkpoint inhibitor therapy has caused large alterations in the oncology therapy landscape. Studies investigating combinations and additional targets may contribute to even more beneficial results for patients by revealing strategies to overcome resistance to immune checkpoint inhibitor therapy. &ldquo;There is an assumption that the type of resistance that one gets to single-agent therapy is probably the same as it is to combination immune checkpoint therapy, and I think that that&rsquo;s probably a fallacy,&rdquo; explained Gibbons. &ldquo;It&rsquo;s important to think about the fact that the types of resistance we see in one setting may not be the same as in another.&rdquo;

Recent studies have shed light on new combinations and targets for immuno-therapy, including targeting CD38 to op- timize PD-1/PD-L1 and CTLA-4 blockade immunotherapy, investigating combinations of immune checkpoint inhibitors with IL-2 agents or TLR agonists, targeting TIM-3 and investigating the immune landscape of premalignant lesions to better predict progression to cancer.

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West EE, Jin HT, Rasheed AU, et al. PD-L1 blockade synergizes with IL-2 therapy in reinvigorating exhausted T cells. J Clin Invest. 2013;123(6):2604-2615. doi: 10.1172/JCI67008.

Desbois M, Le Vu P, Coutzac C, et al. IL-15 trans-signaling with the superagonist RLI promotes effector/memory CD8+ T cell re- sponses and enhances antitumor activity of PD-1 antagonists. J Immunol. 2016;197(1):168-178. doi: 10.4049/jimmunol.1600019.

Mathios D, Park CK, Marcus WD, et al. Therapeutic admin- istration of IL-15 superagonist complex ALT-803 leads to long- term survival and durable antitumor immune response in a mu- rine glioblastoma model. Int J Cancer. 2016;138(1):187-194. doi: 10.1002/ijc.29686.

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Over the last decade, immunotherapeutic options have led to impressive clinical responses in patients with various cancer types and this has increased expectations for successful treatment of the disease. Despite immunotherapy results leading to clinical trials in melanoma, renal cell carcinoma and non&ndash;small cell lung cancer, the percentage of patients who respond to immunotherapy remains low; this highlights the need to identify the patient population that will best respond to these approaches.

Erin M. Burns, PhD, MSPH | Authors

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