MON-181 Clinical Features of Immune Checkpoint Inhibitor-Related Adrenal Insufficiency: A Retrospective Analysis

Abstract Background: Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment over the past decade. Despite their increasing use in clinical practice, there are few established, evidence-based guidelines for the screening and management of immune-related adverse events (irAEs), particularly with regard to autoimmune endocrinopathies. Adrenal insufficiency is an irAE that is poorly characterized due to the nonspecific nature of its presentation and can be life-threatening if not promptly recognized and treated. Our aim is to better define the clinical, biochemical, and imaging features of ICI-related adrenal insufficiency (AI) to mediate earlier recognition and treatment. Methods: We identified a total of 54 patients treated with either nivolumab, pembrolizumab, or ipilimumab combination therapy between January 2010 and August 2018 found to have a random cortisol level less than 2 or morning cortisol less than 5 during or following therapy. Patients who had been on prednisone or dexamethasone at the time of cortisol testing, had a history of adrenalectomy or radiation to the adrenal glands, or had adrenal or pituitary metastasis were excluded. Results: 11 patients met criteria for new onset ICI-related AI based on clinical and biochemical findings. 78% were formally diagnosed with AI, 61% had subsequent workup with ACTH, 17% had dedicated MRI pituitary imaging, 22% had HPA axis testing, 50% were referred to Endocrinology, and 45% were appropriately treated with hydrocortisone. Mean time to onset was 137 days from initiation of ICI. Peripheral eosinophilia was observed in 55% of patients. No anti-21 hydroxylase antibodies were drawn, and no patients had known underlying autoimmune disease or auto-antibody positivity. Six patients (55%) were felt to have secondary AI from ICI-related hypophysitis and one patient (9%) was felt to have ICI-related adrenalitis. Conclusions: As ICIs are being used with increasing frequency, it is crucial for health care providers to recognize the characteristics of immune-mediated adrenal insufficiency and initiate the appropriate workup, treatment, and referrals. Cortisol levels are routinely ordered as part of screening of ICI infusion but often dismissed without proper workup or follow up when levels meet criteria for AI. Our findings suggest that ICI-related AI more frequently manifests as ACTH deficiency in the context of hypophysitis, though primary AI can occur as well. Ultimately, further investigation is necessary to develop a systematic approach to diagnosing and managing ICI-related AI. References: 1. Chang et al. Endocrine Toxicity of Cancer Immunotherapy Targeting Immune Checkpoints. Endocr Rev. 2019;40(1):17-65. 2. Castinetti et al. French Endocrine Society Guidance on endocrine side-effects of immunotherapy. Endocr Relat Cancer. 2018;26(2):G1-G8.

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Immune-related adverse events associated with immune checkpoint inhibitors in patients with cancer

Tumori Journal ◽

10.1177/0300891620953468 ◽

2020 ◽

pp. 030089162095346

Author(s):

Nilay Sengul Samanci ◽

Duygu Ilke Cikman ◽

Kerem Oruc ◽

Sahin Bedir ◽

Emir Çelik ◽

...

Keyword(s):

Adverse Events ◽

Health Care Providers ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Early Recognition ◽

Care Providers ◽

Patients With Cancer ◽

Combination Treatments ◽

Grade 3

Introduction: With the widespread use of immune checkpoint inhibitors (ICIs), we are facing challenges in the management of immune-related adverse events (irAEs). We aimed to characterize the spectrum of toxicity, management, and outcomes for irAEs. Methods: Patients who were treated with at least one ICI in clinical trials, expanded access programs, or routine clinical practice were included. Clinical and laboratory parameters were collected retrospectively to determine the incidence of irAEs, methods of management, and treatment outcomes. Results: A total of 255 patients were screened retrospectively. Of these, 71 (27.8%) patients developed irAEs. More than 2 different types of irAEs were detected in 16 (6.2%) out of 255 patients. A total of 3177 doses were given to 255 patients. In 93 (2.9%) of the 3177 doses, 1 episode of irAEs was experienced. A total of 22 out of 93 (23.7%) episodes were reported as grade 1, 49 (52.7%) as grade 2, 19 (20.4%) as grade 3, and 3 (3.2%) as grade 4. The most frequently seen irAEs were pneumonitis, hepatitis, and hypothyroidism. With regard to treatment, 39 out of 93 episodes (42%) of any grade irAEs occurred after anti–programmed cell death-1 therapy, 47 (50.5%) occurred following administration of anti–programmed death-ligand 1, and 7 (7.5%) occurred after combination treatments. Conclusion: With the increased use of immunotherapeutic agents, increased awareness and early recognition are required for effective management of irAEs. Our experience as a single institution might be of use for health care providers in oncology.

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SAT-242 Isolated Adrenocorticotropic Hormone Deficiency Secondary to the PD-1 Inhibitor Pembrolizumab

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.979 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Justin Mathew ◽

Priyanka Mathias ◽

Noah Bloomgarden

Keyword(s):

Adrenal Insufficiency ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Hormone Deficiency ◽

Immune Checkpoints ◽

Laboratory Evaluation ◽

Advanced Malignancy ◽

Isolated Acth Deficiency ◽

Acth Deficiency

Abstract Background: Immune checkpoint inhibitors (ICI’s) are now indicated in the treatment of several solid tumors and have improved the prognosis of patients with advanced malignancy. The expanded use of ICI’s has led to the rise of otherwise rare autoimmune sequelae. The overall incidence of ICI-induced autoimmune hypophysitis has increased to approximately 10%, but is only estimated to be 0.4% with PD-1 inhibitors specifically (1). Isolated ACTH deficiency from immune checkpoint inhibitors is rare, and very few cases secondary to the PD-1 inhibitor pembrolizumab have thus far been reported. Clinical Case: A 75-year old woman with history of Stage IV lung adenocarcinoma presented to oncology clinic in July 2019 with progressive weakness, weight loss, and confusion for several weeks. She was found to be hypotensive and dehydrated in the clinic and subsequently was admitted to the hospital. A comprehensive infectious work-up was non-contributory. History revealed that after treatment failure with carboplatin, she was treated with pembrolizumab from January 2017 to June 2019 with excellent response. Laboratory evaluation on admission demonstrated an undetectable AM cortisol level of < 1 ug/dL (n 5-25 ug/dL) with concomitant ACTH < 5pg/mL (Roche cobas, n 7.2-63 pg/mL), consistent with central adrenal insufficiency. Testing of the remainder of the pituitary axis, including TSH (0.83uU/mL, n 0.4-4.6 uU/mL), FSH (34.7 mIU/mL, n <150mIU/mL), LH (12.6mIU/mL, n <60 mIU/mL), and IGF-1 (33ng/mL, n 34-245ng/mL), all returned within normal limits. Further chart review verified that she had not been exposed to any form of glucocorticoids within the past 6 months. MRI brain with contrast demonstrated no obvious pituitary disease. The patient was started on 5mg of prednisone daily, with significant improvement in mental status, appetite, and blood pressure. She was discharged home on maintenance prednisone for adrenal insufficiency due to presumed isolated corticotroph destruction. Conclusions: Isolated ACTH deficiency is a very rare but potential consequence of pembrolizumab use. It can be especially difficult to diagnose in patients on chemotherapy who are at higher risk for dehydration and failure to thrive. Duration of pembrolizumab therapy should not preclude the diagnosis of isolated ACTH deficiency, as it can occur even as late as 2.5 years into therapy. Reference: (1) Chang, L., Barroso-Sousa, R., Tolaney S., Hodi F.S., Kaiser, U.B., Min, L. Endocrine Toxicity of Cancer Immunotherapy Targeting Immune Checkpoints, Endocr Rev. 2019;40;17–65.

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Gastrointestinal adverse events associated with immune checkpoint inhibitor therapy

Gastroenterology Report ◽

10.1093/gastro/goz065 ◽

2019 ◽

Vol 8 (1) ◽

pp. 25-30 ◽

Cited By ~ 5

Author(s):

Eva Rajha ◽

Patrick Chaftari ◽

Mona Kamal ◽

Julian Maamari ◽

Christopher Chaftari ◽

...

Keyword(s):

Adverse Events ◽

Health Care Providers ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Care Providers ◽

Organ Systems ◽

Checkpoint Inhibitor Therapy ◽

Recent Addition ◽

Gastrointestinal Adverse Events

Abstract Immunotherapy with checkpoint inhibitors has revolutionized cancer therapy and is now the standard treatment for several different types of cancer, supported by favorable outcomes and good tolerance. However, it is linked to multiple immune manifestations, referred to as immune-related adverse events (irAEs). These adverse events frequently affect the skin, colon, endocrine glands, lungs, and liver. The gastrointestinal system is one of the most commonly affected organ systems and is responsible for the most frequent emergency visits resulting from irAEs. However, because immune checkpoint inhibitors are a recent addition to our arsenal of cancer drugs, many health-care providers remain unfamiliar with the management of irAEs. Gastroenterologists involved in the treatment of oncology patients who have received checkpoint inhibitors are currently encountering cases of abdominal pain, diarrhea, and other nonspecific symptoms that may be challenging to manage. This article reviews the gastrointestinal, hepatic, and pancreatic toxicities of checkpoint inhibitors and provides an approach to their diagnosis and recommended workup. It also highlights the management of irAEs according to their toxicity grading and specifically discusses the instances in which corticosteroids should be administered and/or the immune checkpoint inhibitors should be withheld.

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Immune checkpoint and checkpoint inhibitors in hepatocellular carcinoma

Thai Journal of Hepatology ◽

10.30856/th.jhep2018vol1iss1_07 ◽

2018 ◽

Vol 1 (1) ◽

pp. 28-32

Author(s):

Piyawat Komolmit

Keyword(s):

Hepatocellular Carcinoma ◽

T Cells ◽

Major Histocompatibility Complex ◽

T Cell Receptor ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Cell Receptor ◽

Immune Checkpoints ◽

Histocompatibility Complex

การรักษามะเร็งด้วยแนวความคิดของการกระตุ้นให้ภูมิต้านทานของร่างกายไปทำลายเซลล์มะเร็งนั้น ปัจจุบันได้รับการพิสูจน์ชัดว่าวิธีการนี้สามารถหยุดยั้งการแพร่กระจายของเซลล์มะเร็ง โดยไม่ก่อให้เกิดภาวะแทรกซ้อนทางปฏิกิริยาภูมิต้านทานต่ออวัยวะส่วนอื่นที่รุนแรง สามารถนำมาใช้ทางคลินิกได้ ยุคของการรักษามะเร็งกำลังเปลี่ยนจากยุคของยาเคมีบำบัดเข้าสู่การรักษาด้วยภูมิต้านทาน หรือ immunotherapy ยากลุ่ม Immune checkpoint inhibitors โดยเฉพาะ PD-1 กับ CTLA-4 inhibitors จะเข้ามามีบทบาทในการรักษามะเร็งตับในระยะเวลาอันใกล้ จำเป็นแพทย์จะต้องมีความรู้ความเข้าใจในพื้นฐานของ immune checkpoints และยาที่ไปยับยั้งโมเลกุลเหล่านี้ Figure 1 เมื่อ T cells รับรู้แอนทิเจนผ่านทาง TCR/MHC จะมีปฏิกิริยาระหว่าง co-receptors หรือ immune checkpoints กับ ligands บน APCs หรือ เซลล์มะเร็ง ทั้งแบบกระตุ้น (co-stimulation) หรือยับยั้ง (co-inhibition) TCR = T cell receptor, MHC = major histocompatibility complex

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Immune Checkpoint Inhibitors in Patients with Recurrent Hepatocellular Carcinoma after Liver Transplantation: A Case Report and Literature Review

Current Cancer Drug Targets ◽

10.2174/1568009620666200520084415 ◽

2020 ◽

Vol 20 (9) ◽

pp. 720-727

Author(s):

Jianguo Qiu ◽

Wei Tang ◽

Chengyou Du

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Transplantation ◽

Immune Checkpoint ◽

Graft Rejection ◽

Checkpoint Inhibitors ◽

Liver Graft ◽

Immune Checkpoints ◽

Term Survival ◽

Liver Preservation ◽

Programmed Death

Background: Immune checkpoint modulators, such as the programmed death protein-1 (PD-1)/programmed death ligand-1 (PD-L1) inhibitor, cytotoxic T-Lymphocyte-associated antigen 4 (CTLA-4) inhibitor have been investigated with encouraging results for hepatocellular carcinoma (HCC). However, the safety of this strategy in patients with previous liver transplantation (LT) is not well studied. Objective: To explore the safety and feasibility of immune checkpoints inhibitors in recurrent and metastatic HCC patients on a background of LT. Methods: A case of recurrent, refractory, metastatic HCC after LT, where PD-1 inhibitor was initiated, was described and related literature was reviewed. Results: There was complete remission in lung metastases and the partial radiological response of metastatic retroperitoneal lymph node to the drug with no liver graft rejection after 13 cycles of PD- 1 inhibitor injection. PD-1inhibitor, at least in this patient, was verified to play an important role in controlling tumor progression and prolonging patient survival. Conclusions: This novel drug might be a useful method to allow doctors to guarantee a better chance for long-term survival in recurrent, metastatic HCC patients with the previous LT. However, it should be used with caution in allograft recipients due to the risk of acute graft rejection, further larger, prospective studies are needed to determine optimal immunomodulatory therapy to achieve optimal anti-tumor efficacy with transplant liver preservation.

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From Oncogenic Signaling Pathways to Single-Cell Sequencing of Immune Cells: Changing the Landscape of Cancer Immunotherapy

Molecules ◽

10.3390/molecules26082278 ◽

2021 ◽

Vol 26 (8) ◽

pp. 2278

Author(s):

Afshin Derakhshani ◽

Zeinab Rostami ◽

Hossein Safarpour ◽

Mahdi Abdoli Shadbad ◽

Niloufar Sadat Nourbakhsh ◽

...

Keyword(s):

Single Cell ◽

Signaling Pathways ◽

Immune Cells ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Cancer Development ◽

Immune Checkpoints ◽

Single Cell Sequencing ◽

Increased Risk

Over the past decade, there have been remarkable advances in understanding the signaling pathways involved in cancer development. It is well-established that cancer is caused by the dysregulation of cellular pathways involved in proliferation, cell cycle, apoptosis, cell metabolism, migration, cell polarity, and differentiation. Besides, growing evidence indicates that extracellular matrix signaling, cell surface proteoglycans, and angiogenesis can contribute to cancer development. Given the genetic instability and vast intra-tumoral heterogeneity revealed by the single-cell sequencing of tumoral cells, the current approaches cannot eliminate the mutating cancer cells. Besides, the polyclonal expansion of tumor-infiltrated lymphocytes in response to tumoral neoantigens cannot elicit anti-tumoral immune responses due to the immunosuppressive tumor microenvironment. Nevertheless, the data from the single-cell sequencing of immune cells can provide valuable insights regarding the expression of inhibitory immune checkpoints/related signaling factors in immune cells, which can be used to select immune checkpoint inhibitors and adjust their dosage. Indeed, the integration of the data obtained from the single-cell sequencing of immune cells with immune checkpoint inhibitors can increase the response rate of immune checkpoint inhibitors, decrease the immune-related adverse events, and facilitate tumoral cell elimination. This study aims to review key pathways involved in tumor development and shed light on single-cell sequencing. It also intends to address the shortcomings of immune checkpoint inhibitors, i.e., their varied response rates among cancer patients and increased risk of autoimmunity development, via applying the data from the single-cell sequencing of immune cells.

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Recent Advances and Future Prospects in Immune Checkpoint (ICI)-Based Combination Therapy for Advanced HCC

Cancers ◽

10.3390/cancers13081949 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1949

Author(s):

Yawen Dong ◽

Jeffrey Sum Lung Wong ◽

Ryohichi Sugimura ◽

Ka-On Lam ◽

Bryan Li ◽

...

Keyword(s):

Immune Checkpoint ◽

Cytotoxic T Lymphocyte ◽

Checkpoint Inhibitors ◽

Immune Checkpoints ◽

Advanced Hcc ◽

Oncogenic Pathways ◽

Vegf Pathway ◽

And Function ◽

Endothelial Growth Factor

Advanced, unresectable hepatocellular carcinoma has a dismal outcome. Multiple immune checkpoint inhibitors (ICIs) targeting the programmed-cell death 1 pathway (PD-1/L1) have been approved for the treatment of advanced HCC. However, outcomes remain undesirable and unpredictable on a patient-to-patient basis. The combination of anti-PD-1/L1 with alternative agents, chiefly cytotoxic T-lymphocyte antigen-4 (CTLA-4) ICIs or agents targeting other oncogenic pathways such as the vascular endothelial growth factor (VEGF) pathway and the c-MET pathway, has, in addition to the benefit of directly targeting alterative oncogenic pathways, in vitro evidence of synergism through altering the genomic and function signatures of T cells and expression of immune checkpoints. Several trials have been completed or are underway evaluating such combinations. Finally, studies utilizing transcriptomics and organoids are underway to establish biomarkers to predict ICI response. This review aims to discuss the biological rationale and clinical advances in ICI-based combinations in HCCs, as well as the progress and prospects of the search for the aforementioned biomarkers in ICI treatment of HCC.

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Immune checkpoint inhibitor combination therapies very frequently induce secondary adrenal insufficiency

Scientific Reports ◽

10.1038/s41598-021-91032-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Katsunori Manaka ◽

Junichiro Sato ◽

Maki Takeuchi ◽

Kousuke Watanabe ◽

Hidenori Kage ◽

...

Keyword(s):

Combination Therapy ◽

Adrenal Insufficiency ◽

Cancer Patients ◽

Immune Checkpoint ◽

Checkpoint Inhibitors ◽

Delayed Diagnosis ◽

Secondary Adrenal Insufficiency ◽

Acth Deficiency ◽

Life Threatening ◽

Inhibitor Combination

AbstractImmune checkpoint inhibitors (ICIs) are potent therapeutic options for many types of advanced cancer. The expansion of ICIs use however has led to an increase in immune-related adverse events (irAEs). Secondary adrenal insufficiency (AI) can be life-threatening especially in patients with delayed diagnosis. We retrospectively investigated secondary AI in ICI-treated patients. A total of 373 cancer patients treated with ICIs were included and evaluated. An adrenocorticotropic hormone (ACTH) deficiency was described in 13 patients. Among 24 patients with a combination of nivolumab and ipilimumab therapy, 7 patients (29%) developed secondary AI in a median time of 8 weeks during the combination therapy and 2 of 15 patients (13%) developed isolated ACTH deficiency during maintenance nivolumab monotherapy following the combination therapy. More than half of the patients (4/7) with a combination therapy-induced multiple anterior hormone deficiencies was diagnosed as secondary AI based on regular ACTH and cortisol tests with slight subjective symptoms. Secondary AI can arise frequently and rapidly in cancer patients receiving a combination ICI therapy, and thus we speculate active surveillance of AI using regular ACTH and cortisol tests during the combination therapy might be useful for avoiding life-threatening conditions due to secondary AI.

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A case of cancer-associated hyponatraemia: primary adrenal insufficiency secondary to nivolumab

Endocrine Metabolic & Immune Disorders - Drug Targets ◽

10.2174/1871530321666210708142815 ◽

2021 ◽

Vol 21 ◽

Author(s):

Silvia Galliazzo ◽

Filippo Morando ◽

Paola Sartorato ◽

Michela Bortolin ◽

Ernesto De Menis

Keyword(s):

Adverse Events ◽

Adrenal Insufficiency ◽

Immune Checkpoint ◽

Checkpoint Inhibitors ◽

Serum Cortisol ◽

Sodium Concentration ◽

Primary Hypothyroidism ◽

Biochemical Tests ◽

Primary Adrenal Insufficiency ◽

Replacement Treatment

Background: Immunotherapy with immune checkpoint inhibitors is a new frontier for cancer treatment. On the safety profile, this drug class is associated with a new spectrum of side effects, the so-called immune-related adverse events that can potentially affect any organs, mainly endocrine glands. Scant data are available to inform the appropriate strategy of their management and treatment. Case Presentation: A 74-years man with squamous non-small cell lung cancer on nivolumab was hospitalized for fatigue, nausea, vomiting and severe hyponatremia. Biochemical tests were significant for hypotonic hyponatremia with a high urine sodium concentration. Endocrine tests showed overt primary hypothyroidism and low serum cortisol and aldosterone levels associated with an elevated circulating level of adrenocorticotrophic hormone. Adrenal antibody screening and the search of adrenal lesion on CT abdomen were negative. Thus, a nivolumab-induced primary adrenal insufficiency was diagnosed. Nivolumab withdrawal and replacement treatment with glucocorticoid and mineralocorticoid allowed clinical and biochemical recovery. Conclusion: Physicians need to be aware of potential immune-related adverse events in all patients treated with an immune checkpoint inhibitor. Their timely recognition is essential to carry out the proper treatment.

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281 Measuring immune checkpoint inhibitor efficacy using primary patient-derived 3D spheroids

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-sitc2021.281 ◽

2021 ◽

Vol 9 (Suppl 3) ◽

pp. A305-A305

Author(s):

Kathryn Appleton ◽

Katy Lassahn ◽

Ashley Elrod ◽

Tessa DesRochers

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Immune Checkpoint ◽

Checkpoint Inhibitors ◽

Clinical Success ◽

Single Cells ◽

Granzyme B ◽

Immune Checkpoints ◽

Dependent Manner ◽

Luminex Technology

BackgroundCancerous cells can utilize immune checkpoints to escape T-cell-mediated cytotoxicity. Agents that target PD-1, PD-L1 and CTLA4 are collectively deemed immune checkpoint inhibitors (ICIs), and many have been approved for treatment of non-small cell lung cancer (NSCLC) and melanoma. Unfortunately, many patients do not respond to these therapies and often experience disease progression. Immunohistochemistry assays to predict response to ICIs have been inconsistent in their readouts and often patients with low expression levels respond to ICIs. Understanding the determinants of ICI response in individual patients is critical for improving the clinical success of this drug class. Using patient-derived spheroids from NSCLC and melanoma primary tissue, we developed a multi-plexed assay for detecting ICI efficacy.MethodsNine NSCLC and 11 melanoma primary tumor samples were dissociated to single cells, classified for immune checkpoint expression and cell content by flow cytometry, and seeded for spheroid formation. Spheroids were treated with pembrolizumab, nivolumab, atezolizumab, ipilimumab or durvalumab across a range of concentrations and monitored for cytotoxicity at 24-hours and viability at 72-hours by multiplexing CellTox™ Green Cytotoxicity Assay and CellTiter-Glo® 3D Cell Viability Assay. IFNγ and granzyme B secretion was assessed using Luminex technology. ICI response was evaluated by determining the concentration-response relationship for all three read-outs.ResultsIncreased IFNγ and granzyme B were detected for every ICI in one or more patient samples. ICI-induced IFNγ secretion inversely correlated with PD-1+ immune cells. Durvalumab was significantly more cytotoxic for both NSCLC and melanoma spheroids compared to the other ICIs and significantly reduced spheroid viability with mean spheroid survival decreasing to 19.5% for NSCLC and 58.2% for melanoma. We evaluated if there was an association between durvalumab response and cell composition and found that percent spheroid survival significantly correlated with CD8+ T-cells for both NSCLC (r=-0.7920, p=0.0191) and melanoma (r=-0.6918, p=0.0390). Furthermore, CD8+ T-cells correlated with durvalumab-induced granzyme B secretion for NSCLC (r=-0.7645, p=0.0271) and melanoma (r=-0.7419, p=0.0221).ConclusionsIn this study we show ICI-specific increases in immune-related analytes in a concentration-dependent manner for NSCLC and melanoma patient-derived spheroids. We detected spheroid cytotoxicity following short term ICI treatment which closely mirrored decreased spheroid viability at a later timepoint. Finally, we can decipher response mechanisms as exemplified by durvalumab-induced granzyme B secretion correlating with the presence of CD8+ T-cells which results in reduced spheroid viability for both tested cancer indications.

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