The future of targeting cytotoxic T-lymphocyte-associated protein-4: Is there a role?

The 2022 yearly Think Tank Meeting in Siena, Tuscany (Italy), organized by the Italian Network for Tumor Biotherapy (NIBIT) Foundation, the Parker Institute for Cancer Immunotherapy and the World Immunotherapy Council, included a focus on the future of integrating and expanding the use of targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). The conference members exchanged their views on the lessons from targeting CTLA-4 and compared the effect to the impact of blocking Programmed cell death protein 1 (PD1) or its ligand (PDL1). The increasing experience with both therapeutic approaches and their combination suggests that targeting CTLA-4 may lead to more durable responses for a sizeable proportion of patients, though the specific mechanism is not entirely understood. Overcoming toxicity of blocking CTLA-4 is currently being addressed with different doses and dose regimens, especially when combined with PD1/PDL1 blocking antibodies. Novel therapeutics targeting CTLA-4 hold the promise to reduce toxicities and thus allow different combination strategies in the future. On the whole, the consent was that targeting CTLA-4 remains an important strategy to improve the efficacy of cancer immunotherapies.

Immunotherapy for brain metastases and primary brain tumors.

During the V Siena Immuno-Oncology (IO) Think Tank meeting in 2021, conditions were discussed which favor immunotherapy responses in either primary or secondary brain malignancies. Core elements of these discussions have been reinforced by important publications in 2021 and 2022. In primary brain tumors (such as glioblastoma) current immunotherapies have failed to deliver meaningful clinical benefit. By contrast, brain metastases frequently respond to current immunotherapies. The main differences between both conditions seem to be related to intrinsic factors (e.g., type of driver mutations) and more importantly extrinsic factors, such as the blood brain barrier and immune suppressive microenvironment (e.g., T cell counts, functional differences in T cells, myeloid cells). Future therapeutic interventions may therefore focus on rebalancing the immune cell population in a way which enables the host to respond to current or future immunotherapies.

Correction: Vancomycin Flushing Syndrome Due to Oral Vancomycin in Chronic Kidney Disease Patients: A Case Report.

[This corrects the article DOI: 10.7759/cureus.28024.].

Red Man Syndrome Due to Oral Vancomycin in Chronic Kidney Disease Patients: A Case Report.

The red man syndrome is a known complication of vancomycin. It is commonly seen with intravenous (IV) use but is also documented with oral use. We aim to describe a case of a chronic kidney disease (CKD) patient who developed red man syndrome secondary to oral vancomycin use. Our case is about an immunosuppressed 68-year-old man who received oral vancomycin for pseudomembranous colitis, which was caused by Clostridium difficile. On the eighth day of the treatment, the patient experienced pruritus and an erythematous rash, which was diagnosed as red man syndrome, and the oral vancomycin was immediately discontinued. Upon the discontinuation of the drug, the rash disappeared, thus confirming the diagnosis. The patient's status of chronic kidney disease stage four resulted in reduced clearance of the drug, thus causing the adverse effect. This case highlights the importance of prophylaxis to prevent red man syndrome in a chronic kidney disease patient. Red man syndrome is commonly seen after the initiation of vancomycin, ciprofloxacin, or amphotericin B. Prompt diagnosis and management are required to prevent the complications due to this condition.

Superior Vena Cava Syndrome Due to Right Anterior Mediastinal Hematoma: A Case Report.

The superior vena cava syndrome (SVCS) has been frequently reported to be secondary to malignancy, specifically, small cell bronchogenic carcinoma and non-Hodgkin's lymphoma. There is some data suggesting causes like postprocedural hematomas. We aim to describe a case of a patient who developed SVCS secondary to a mediastinal hematoma secondary to epicardial pacer leads (postprocedural). Our case is about a 75-year-old male with a past medical history of coronary artery disease and coronary artery bypass graft (CABG) who presented to the Emergency Department (ED) with moderate-to-severe right axillary pain radiating to the ipsilateral side of the neck, arm, and chest, associated to right temporal headache. A computed tomography angiography (CTA) of the chest was indicated at the time and revealed a hematoma with an active extravasation within the right superior anterior mediastinum, outside the pericardium. The patient was admitted to the Cardiovascular Intensive Care Unit (CVICU) and was started on nicardipine as his blood pressure in the ED was 217/125 and remained elevated despite proper pain management. A repeat CT scan of the chest showed a regressing hematoma that coincided with an improvement of the symptoms. This case highlights the importance of the complications of anterior mediastinal hematoma. The superior vena cava syndrome can develop after cardiologic procedures, after the implantation of devices. Prompt clinical diagnosis, including imaging, and treatment are necessary to manage this condition.

Sotigalimab and/or nivolumab with chemotherapy in first-line metastatic pancreatic cancer: clinical and immunologic analyses from the randomized phase 2 PRINCE trial.

Chemotherapy combined with immunotherapy has improved the treatment of certain solid tumors, but effective regimens remain elusive for pancreatic ductal adenocarcinoma (PDAC). We conducted a randomized phase 2 trial evaluating the efficacy of nivolumab (nivo; anti-PD-1) and/or sotigalimab (sotiga; CD40 agonistic antibody) with gemcitabine/nab-paclitaxel (chemotherapy) in patients with first-line metastatic PDAC ( NCT03214250 ). In 105 patients analyzed for efficacy, the primary endpoint of 1-year overall survival (OS) was met for nivo/chemo (57.7%, P = 0.006 compared to historical 1-year OS of 35%, n = 34) but was not met for sotiga/chemo (48.1%, P = 0.062, n = 36) or sotiga/nivo/chemo (41.3%, P = 0.223, n = 35). Secondary endpoints were progression-free survival, objective response rate, disease control rate, duration of response and safety. Treatment-related adverse event rates were similar across arms. Multi-omic circulating and tumor biomarker analyses identified distinct immune signatures associated with survival for nivo/chemo and sotiga/chemo. Survival after nivo/chemo correlated with a less suppressive tumor microenvironment and higher numbers of activated, antigen-experienced circulating T cells at baseline. Survival after sotiga/chemo correlated with greater intratumoral CD4 T cell infiltration and circulating differentiated CD4 T cells and antigen-presenting cells. A patient subset benefitting from sotiga/nivo/chemo was not identified. Collectively, these analyses suggest potential treatment-specific correlates of efficacy and may enable biomarker-selected patient populations in subsequent PDAC chemoimmunotherapy trials.

Ipilimumab alone or in combination with nivolumab in patients with advanced melanoma who have progressed or relapsed on PD-1 blockade: clinical outcomes and translational biomarker analyses.

BACKGROUND: There are no validated biomarkers that can aid clinicians in selecting who would best benefit from anticytotoxic T lymphocyte-associated antigen 4 monotherapy versus combination checkpoint blockade in patients with advanced melanoma who have progressive disease after programmed death 1 (PD-1) blockade. METHODS: We conducted a randomized multicenter phase II trial in patients with advanced melanoma. Patients were randomly assigned to receive either 1 mg/kg of nivolumab plus 3 mg/kg of ipilimumab or 3 mg/kg of ipilimumab every 3 weeks for up to four doses. Patients were stratified by histological subtype and prior response to PD-1 therapy. The primary clinical objective was overall response rate by week 18. Translational biomarker analyses were conducted in patients with blood and tissue samples. RESULTS: Objective responses were seen in 5 of 9 patients in the ipilimumab arm and 2 of 10 patients in the ipilimumab+nivolumab arm; disease control rates (DCRs) (66.7% vs 60.0%) and rates of grade 3-4 adverse events (56% vs 50%) were comparable between arms. In a pooled analysis, patients with clinical benefit (CB), defined as Response Evaluation Criteria in Solid Tumors response or progression-free for 6 months, showed increased circulating CD4+ T cells with higher polyfunctionality and interferon gamma production following treatment. Tumor profiling revealed enrichment of NRAS mutations and activation of transcriptional programs associated with innate and adaptive immunity in patients with CB. CONCLUSIONS: In patients with advanced melanoma that previously progressed on PD-1 blockade, objective responses were seen in both arms, with comparable DCRs. Findings from biomarker analyses provided hypothesis-generating signals for validation in future studies of larger patient cohorts. TRIAL REGISTRATION NUMBER: NCT02731729.

A vision of immuno-oncology: the Siena think tank of the Italian network for tumor biotherapy (NIBIT) foundation.

BACKGROUND: The yearly Think Tank Meeting of the Italian Network for Tumor Biotherapy (NIBIT) Foundation, brings together in Siena, Tuscany (Italy), experts in immuno-oncology to review the learnings from current immunotherapy treatments, and to propose new pre-clinical and clinical investigations in selected research areas. MAIN: While immunotherapies in non-small cell lung cancer and melanoma led to practice changing therapies, the same therapies had only modest benefit for patients with other malignancies, such as mesothelioma and glioblastoma. One way to improve on current immunotherapies is to alter the sequence of each combination agent. Matching the immunotherapy to the host's immune response may thus improve the activity of the current treatments. A second approach is to combine current immunotherapies with novel agents targeting complementary mechanisms. Identifying the appropriate novel agents may require different approaches than the traditional laboratory-based discovery work. For example, artificial intelligence-based research may help focusing the search for innovative and most promising combination partners. CONCLUSION: Novel immunotherapies are needed in cancer patients with resistance to or relapse after current immunotherapeutic drugs. Such new treatments may include targeted agents or monoclonal antibodies to overcome the immune-suppressive tumor microenvironment. The mode of combining the novel treatments, including vaccines, needs to be matched to the patient's immune status for achieving the maximum benefit. In this scenario, specific attention should be also paid nowadays to the immune intersection between COVID-19 and cancer.

Neoadjuvant immunotherapy is reshaping cancer management across multiple tumour types: The future is now!

The Italian Network for Tumor Biotherapy (Network Italiano per la Bioterapia dei Tumori [NIBIT]) Foundation hosted its annual 2020 Think Tank meeting virtually, at which representatives from academic, clinical, industry, philanthropic, and regulatory organisations discussed the role of neoadjuvant immunotherapy for the treatment of cancer. Although the number of neoadjuvant immunotherapeutic trials is increasing across all malignancies, the Think Tank focused its discussion on the status of neoadjuvant trials in cutaneous melanoma (CM), muscle-invasive urothelial bladder cancer (MIBC), head and neck squamous cell carcinoma (HNSCC), and pancreatic adenocarcinoma (PDAC). Neoadjuvant developments in CM are nothing short of trailblazing. Pathologic Complete Response (pCR), pathologic near Complete Response, and partial Pathologic Responses reduce 90-100% of recurrences. This is in sharp contrast to targeted therapies in neoadjuvant CM trials, where only a pCR seems to reduce recurrence. The pCR rate after neoadjuvant immunotherapy varies among the different malignancies of CM, MIBC, HNSCC, and PDAC and may be associated with different reductions of recurrence rates. In CM, emerging evidence suggests that neoadjuvant immunotherapy with anti-CTLA-4 plus anti-PD1 is a game changer in patients with palpable nodal Stage III or resectable Stage IV disease by curing more patients, reducing recurrences and the need for surgical interventions, such as lymph node dissections and metastasectomies. The Think Tank panel discussed future approaches on how to optimise results across different tumour types. Future approaches should include reducing monocyte-mediated (tumour-associated macrophages) and fibroblast-mediated (cancer-associated fibroblasts) barriers in the tumour microenvironment to facilitate the recruitment of immune cells to the tumour site, to reduce immune-suppressive mediators, and to increase antigen presentation at the site of the tumour.

CD40 agonistic monoclonal antibody APX005M (sotigalimab) and chemotherapy, with or without nivolumab, for the treatment of metastatic pancreatic adenocarcinoma: an open-label, multicentre, phase 1b study.

BACKGROUND: Standard chemotherapy remains inadequate in metastatic pancreatic adenocarcinoma. Combining an agonistic CD40 monoclonal antibody with chemotherapy induces T-cell-dependent tumour regression in mice and improves survival. In this study, we aimed to evaluate the safety of combining APX005M (sotigalimab) with gemcitabine plus nab-paclitaxel, with and without nivolumab, in patients with pancreatic adenocarcinoma to establish the recommended phase 2 dose. METHODS: This non-randomised, open-label, multicentre, four-cohort, phase 1b study was done at seven academic hospitals in the USA. Eligible patients were adults aged 18 years and older with untreated metastatic pancreatic adenocarcinoma, Eastern Cooperative Oncology Group performance status score of 0-1, and measurable disease by Response Evaluation Criteria in Solid Tumors version 1.1. All patients were treated with 1000 mg/m2 intravenous gemcitabine and 125 mg/m2 intravenous nab-paclitaxel. Patients received 0·1 mg/kg intravenous APX005M in cohorts B1 and C1 and 0·3 mg/kg in cohorts B2 and C2. In cohorts C1 and C2, patients also received 240 mg intravenous nivolumab. Primary endpoints comprised incidence of adverse events in all patients who received at least one dose of any study drug, incidence of dose-limiting toxicities (DLTs) in all patients who had a DLT or received at least two doses of gemcitabine plus nab-paclitaxel and one dose of APX005M during cycle 1, and establishing the recommended phase 2 dose of intravenous APX005M. Objective response rate in the DLT-evaluable population was a key secondary endpoint. This trial (PRINCE, PICI0002) is registered with ClinicalTrials.gov, NCT03214250 and is ongoing. FINDINGS: Between Aug 22, 2017, and July 10, 2018, of 42 patients screened, 30 patients were enrolled and received at least one dose of any study drug; 24 were DLT-evaluable with median follow-up 17·8 months (IQR 16·0-19·4; cohort B1 22·0 months [21·4-22·7], cohort B2 18·2 months [17·0-18·9], cohort C1 17·9 months [14·3-19·7], cohort C2 15·9 months [12·7-16·1]). Two DLTs, both febrile neutropenia, were observed, occurring in one patient each for cohorts B2 (grade 3) and C1 (grade 4). The most common grade 3-4 treatment-related adverse events were lymphocyte count decreased (20 [67%]; five in B1, seven in B2, four in C1, four in C2), anaemia (11 [37%]; two in B1, four in B2, four in C1, one in C2), and neutrophil count decreased (nine [30%]; three in B1, three in B2, one in C1, two in C2). 14 (47%) of 30 patients (four each in B1, B2, C1; two in C2) had a treatment-related serious adverse event. The most common serious adverse event was pyrexia (six [20%] of 30; one in B2, three in C1, two in C2). There were two chemotherapy-related deaths due to adverse events: one sepsis in B1 and one septic shock in C1. The recommended phase 2 dose of APX005M was 0·3 mg/kg. Responses were observed in 14 (58%) of 24 DLT-evaluable patients (four each in B1, C1, C2; two in B2). INTERPRETATION: APX005M and gemcitabine plus nab-paclitaxel, with or without nivolumab, is tolerable in metastatic pancreatic adenocarcinoma and shows clinical activity. If confirmed in later phase trials, this treatment regimen could replace chemotherapy-only standard of care in this population. FUNDING: Parker Institute for Cancer Immunotherapy, Cancer Research Institute, and Bristol Myers Squibb.

Immune Checkpoint Inhibitors for Cancer Therapy in the COVID-19 Era.

The potential immune intersection between COVID-19 disease and cancer therapy raises important practical clinical questions and highlights multiple scientific gaps to be filled. Among available therapeutic approaches to be considered, immune checkpoint inhibitors (ICI) seem to require major attention as they may act at the crossroads between cancer treatment and COVID-19 disease, due to their profound immunomodulatory activity. On the basis of available literature evidence, we suggest guidance to consider for treating physicians, and propose areas of clinical and preclinical investigation. Comprehensively, although with the necessary caution, ICI therapy seems to remain a suitable therapeutic option for patients with cancer during the COVID-19 pandemic.

Accelerating the development of innovative cellular therapy products for the treatment of cancer.

The field of cell therapy is rapidly emerging as a priority area for oncology research and drug development. Currently, two chimeric antigen receptor T-cell therapies are approved by the US Food and Drug Administration and other agencies worldwide for two types of hematologic cancers. To facilitate the development of these therapies for patients with life-threatening cancers with limited or no therapeutic options, science- and risk-based approaches will be critical to mitigating and balancing any potential risk associated with either early clinical research or more flexible manufacturing paradigms. Friends of Cancer Research and the Parker Institute for Cancer Immunotherapy convened an expert group of stakeholders to develop specific strategies and proposals for regulatory opportunities to accelerate the development of cell therapies as promising new therapeutics. This meeting took place in Washington, DC on May 17, 2019. As academia and industry expand research efforts and cellular product development pipelines, this report summarizes opportunities to accelerate entry into the clinic for exploratory studies and optimization of cell products through manufacturing improvements for these promising new therapies.

The Italian Network for Tumor Bio-Immunotherapy (NIBIT) Foundation: ongoing and prospective activities in immuno-oncology.

The ongoing revolution in cancer immunotherapy stems from the knowledge that distinct immune-checkpoints regulate the physiological crosstalk between and among immune cells by delivering inhibitory or activating signals. These notions, and the availability of mAb directed to diverse immune-checkpoint molecules, have led to a significant clinical improvement in cancer treatment. In this scenario, further achievements are undoubtedly to be expected from the contribution of novel, proof-of-principle clinical trials designed to explore the therapeutic efficacy of new immunotherapy-based combinations and treatment sequences. Along these lines, the clinical translation of pre-clinical evidence generated by non-profit research entities is likely to provide a significant contribution to gaining new insights that will further boost the field of cancer immunotherapy. To pursue this goal, and to provide comprehensive educational programs in immune-oncology (I-O), several national and global networks have been revitalized or newly established in recent years. This rapidly evolving scenario led the Board of Directors of the Italian Network of Tumor Bio-Immunotherapy (NIBIT) to establish the NIBIT Foundation. This Focused Research Review summarizes the main ongoing and prospective I-O activities of the NIBIT Foundation.

Addressing current challenges and future directions in immuno-oncology: expert perspectives from the 2017 NIBIT Foundation Think Tank, Siena, Italy.

A collaborative think tank involving panellists from immuno-oncology networks, clinical/translational investigators and the pharmaceutical industry was held in Siena, Italy, in October 2017 to discuss the evolving immune-oncology landscape, identify selected key challenges, and provide a perspective on the next steps required in the translation of current research and knowledge to clinical reality. While there is a trend of combining new agents (e.g., co-stimulator agonists) with a PD-1/PD-L1 treatment backbone, use of alternative combination therapy approaches should also be considered. While the rapid evolution in systems biology provides a deeper understanding of tumor and tumor microenvironment heterogeneity, there remains the need to identify and define genuinely predictive biomarkers to guide treatment and patient selection. Cross-specialty and cross-sector collaboration, along with a broader collective data-sharing approach are key to optimizing immuno-oncology therapy in clinical practice. Continued support of younger research-clinicians is essential for future success in clinical, translational and basic science investigations.

Future cancer research priorities in the USA: a Lancet Oncology Commission.

We are in the midst of a technological revolution that is providing new insights into human biology and cancer. In this era of big data, we are amassing large amounts of information that is transforming how we approach cancer treatment and prevention. Enactment of the Cancer Moonshot within the 21st Century Cures Act in the USA arrived at a propitious moment in the advancement of knowledge, providing nearly US$2 billion of funding for cancer research and precision medicine. In 2016, the Blue Ribbon Panel (BRP) set out a roadmap of recommendations designed to exploit new advances in cancer diagnosis, prevention, and treatment. Those recommendations provided a high-level view of how to accelerate the conversion of new scientific discoveries into effective treatments and prevention for cancer. The US National Cancer Institute is already implementing some of those recommendations. As experts in the priority areas identified by the BRP, we bolster those recommendations to implement this important scientific roadmap. In this Commission, we examine the BRP recommendations in greater detail and expand the discussion to include additional priority areas, including surgical oncology, radiation oncology, imaging, health systems and health disparities, regulation and financing, population science, and oncopolicy. We prioritise areas of research in the USA that we believe would accelerate efforts to benefit patients with cancer. Finally, we hope the recommendations in this report will facilitate new international collaborations to further enhance global efforts in cancer control.

Paget-Schroetter syndrome in the absence of common predisposing factors: a case report.

BACKGROUND: Paget-Schrotter Syndrome (PSS) also known as "effort thrombosis" is a form of primary thrombosis in the subclavian vein at the costoclavicular junction is usually seen in younger patients after repeated strenuous activity of the shoulders and arms. When occurring in younger patients, PSS presents itself with predisposing factors such as unilateral dull, aching pain in the shoulder or axilla and swelling of the arm and hand. CASE PRESENTATION: We report a rare case of unusual left axillo-subclavian vein thrombosis in absence of clear risk factors and a negative hypercoagulable workup in a 36-year-old Hispanic woman who presented with 2 days duration of left upper extremity pain and swelling after a week of heavy exercise in aerobic class. Very few documented cases of primary or spontaneous ASVT in absence of clear factors and in such anatomical location have been previously reported. The patient was started on strict precautions of left upper extremity immobilization, analgesics in the form of Tylenol 650 mg every 6 h for pain as well as cold compresses. Lovenox 90 mg subcutaneous twice daily (1 mg/kg BID) was started together with warfarin to keep INR 2-3. CONCLUSION: In addition to the unusual location in the left upper extremity in our case, the absence of common etiologic factors makes our case of Paget-Schroetter Syndrome a very unique one. Presently, there is a lack of guided management of rare conditions such as our case, or consensus among the sources. Physicians should be aware of this rare disease since untreated conditions may be debilitating for the patient and very costly especially if diagnosed with a delay.

New Cancer Immunotherapy Agents in Development: a report from an associated program of the 31stAnnual Meeting of the Society for Immunotherapy of Cancer, 2016.

This report is a summary of 'New Cancer Immunotherapy Agents in Development' program, which took place in association with the 31st Annual Meeting of the Society for Immunotherapy of Cancer (SITC), on November 9, 2016 in National Harbor, Maryland. Presenters gave brief overviews of emerging clinical and pre-clinical immune-based agents and combinations, before participating in an extended panel discussion with multidisciplinary leaders, including members of the FDA, leading academic institutions and industrial drug developers, to consider topics relevant to the future of cancer immunotherapy.

Do Sociodemographic Factors Influence Outcome in Prostate Cancer Patients Treated With External Beam Radiation Therapy?

OBJECTIVES: The purpose of this study was to analyze the prognostic significance of sociodemographic factors on biochemical control (bNED) and overall survival (OS) in patients with prostate cancer. METHODS: Prostate cancer patients treated with definitive external beam radiation therapy (EBRT)±hormone therapy from 1997 to 2006 were analyzed in this IRB-approved study. Patient demographics, treatment (Tx), and clinical outcome were obtained from electronic medical records. Median household income (mHHI) at the census block group level was obtained from the 2000 census data. Data on disease and Tx parameters included Gleason score, pre-Tx prostate-specific antigen (PSA), T stage, year of Tx, EBRT dose, and use of hormone therapy. Patients were categorized as having low-risk, intermediate-risk, or high-risk disease. Sociodemographic factors included age, race, marital status, and mHHI. Biochemical failure was defined as nadir PSA+2 ng/mL. OS was based on death from any cause. RESULTS: A total of 788 consecutive patients were studied with a median follow-up of 7 years (range, 0.4 to 15 y). African Americans comprised 48% of the patients, whereas 46% of patients were white and 6% were other races. Whites had an average mHHI of $60,190 compared with $36,917 for African Americans (P<0.001). After multivariable modeling, only radiation dose was predictive for bNED (P=0.004) or OS (P=0.008). No sociodemographic factors were predictive for either outcome. Higher radiation dose predicted for better biochemical control and OS. CONCLUSIONS: This analysis suggests that sociodemographic factors are not important prognostic factors in determining outcome after EBRT for prostate cancer.

PD-L1 blockade for cancer treatment: MEDI4736.

MEDI4736 is a human immunoglobulin (Ig) G1к monoclonal antibody that blocks programmed cell death ligand-1 (PD-L1) binding to its receptors, allowing T cells to recognize and kill tumor cells. Key attributes include high affinity and selectivity for PD-L1, sustained drug exposure for up to 1 year of dosing, and engineering of the antibody to prevent antibody-dependent cell-mediated cytotoxicity. No immunogenicity impacting on the pharmacokinetics/pharmacodynamics of MEDI4736 has been reported at the 10 mg/kg every 2 weeks dose selected for further clinical development. The current safety profile and encouraging early anti-tumor activity of MEDI4736 support further clinical assessment. A broad development program for MEDI4736, both as monotherapy and in combination, is underway across a range of tumor types. This includes a large, multicenter, phase I, dose-escalation/expansion study in solid tumors (with a smaller corresponding study in Japanese patients), a phase I study in myelodysplastic syndrome, and a phase II study in advanced colorectal cancer. In addition, multiple phase I combination studies are ongoing with different agents, including those targeting MEK/BRAF in melanoma, epidermal growth factor receptor, programmed cell death-1, cytotoxic T-lymphocyte antigen-4, OX40, chemokine (C-C motif) receptor 4, and indoleamine 2,3-dioxygenase. Development is most advanced in non-small cell lung cancer, with a program currently comprising four pivotal studies and three phase I combination studies. A pivotal program for MEDI4736 in head and neck cancer began in late 2014.