Hyperprogression under Immunotherapy Frelaut, Maxime; Le Tourneau, Christophe; Borcoman, Edith
International journal of molecular sciences,
05/2019, Letnik:
20, Številka:
11
Journal Article
Recenzirano
Odprti dostop
Immunotherapy is now widely prescribed in oncology, leading to the observation of new types of responses, including rapid disease progression sometimes reported as hyperprogression. However, only a ...few studies have assessed the question of hyperprogression and there is no consensual definition of this phenomenon. We reviewed existing data on hyperprogression in published studies, focusing on reported definitions, predictive factors, and potential biological mechanisms. Seven studies retrospectively assessed hyperprogression incidence, using various definitions, some based on the tumoral burden variation across time with repeated computed-tomography (CT) scan, others based on an association of radiological and clinical criteria. Reported hyperprogression incidence varied between 4% and 29% of all responses, mostly in multi-tumor cohorts and with patients receiving immune checkpoint inhibitors. Hyperprogression correlated with worse chances of survival than standard progression in two studies. However, no strong predictive factors of hyperprogression were identified, and none were consistent across studies. In total, hyperprogression is a frequent pattern of response under immunotherapy, with a strong impact on patient outcome. There is a need for a consensual definition of hyperprogression. Immunotherapy should be stopped early in cases where there is suspicion of hyperprogression.
Cervical cancer is the fourth most common cause of cancer-related deaths in women worldwide. With the development of detection of precancerous lesions and preventive human papillomavirus (HPV) ...vaccination program, a survival improvement has been observed in these patients in developed countries, although disparities in accessibility to treatments exist across countries. While early-stage cervical cancer can be curable with surgery, prognosis of patients who recur remains poor, with limited treatment options. In this latter setting, recently, bevacizumab, an antiangiogenic monoclonal antibody targeting vascular endothelial growth factor (VEGF), has been shown to improve overall survival in combination with chemotherapy as compared with chemotherapy alone. No standard treatments exist beyond this treatment regimen. New effective treatments are therefore much needed in this setting. Immunotherapy has represented a breakthrough in recent years in oncology, with antitumor activity reported with immune-checkpoint inhibitors in a variety of tumor types. We discuss here the latest evidence and clinical usefulness of pembrolizumab, anti-PD-1 checkpoint inhibitor, in the treatment of advanced cervical cancer.
Patterns of response and progression to immunotherapy may differ from those observed with drugs such as chemotherapy and molecularly targeted agents. Specifically, some patients experience a response ...after progression that is retrospectively named pseudoprogression. This phenomenon of pseudoprogression, first reported in patients with melanoma who were treated with ipilimumab, has led to the development of immune-specific related response criteria, such as irRC (immune-related response criteria), irRECIST (immune-related RECIST), and iRECIST (immunotherapy RECIST) that allow continued treatment beyond progression. However, the rate of pseudoprogression has never exceeded 10% of patients across tumor types. Conversely, rapid progressions after immunotherapy, called hyperprogressions, were reported by three different teams in 9% to 29% of patients treated with immunotherapy. Because of the absence of control arms in these studies, it remains to be determined whether these rapid progressions reflect a detrimental effect of immunotherapy in these patients. Finally, preliminary data suggest that immunotherapy might also affect response to subsequent standard therapies. In total, given the rarity of pseudoprogressions across tumor types and the recent description of hyperprogressions, classic RECIST remains a reasonable and rational method to assess response to immunotherapy. Continuation of treatment beyond progression should be proposed only in carefully selected patients whose clinical conditions have improved and who have not experienced severe toxicities. Although there is an urgent need to identify predictive biomarkers of efficacy to immunotherapy, there is an equally urgent need to identify predictive factors of progression or possibly hyperprogression.
Changes in the oral microbiome, particularly Fusobacterium nucleatum, are associated with oral squamous cell carcinoma (OSCC). F. nucleatum has been reported to modulate local immunity in cancers. We ...aimed to assess the association between intratumoral F. nucleatum and clinico-pathological features, relapse, and overall survival (OS) in two independent cohorts of patients with OSCC, and to explore the interplay with immune-related genes. We retrospectively analyzed tissue samples from a first cohort of 122 patients with head and neck squamous cell carcinoma, including 61 OSCC (cohort #1), and a second cohort of 90 additional OSCC (cohort #2). We then performed a sensitivity analysis on the merged cohort of OSCC patients (N = 151). F. nucleatum 16S rRNA gene sequences were quantified using real-time quantitative PCR. The presence of gram-negative bacteria and macrophages was confirmed by LPS and CD163 immunostainings, respectively. F. nucleatum positivity was associated with older age, less alcohol and combined alcohol plus tobacco consumption, and less frequent lymph node invasion. There was a trend for a lower recurrence rate in F. nucleatum-positive cases, with less metastatic relapses compared to F. nucleatum-negative tumors, and significantly longer OS, relapse-free and metastasis-free survival. F. nucleatum status was independently associated with OS in multivariate analysis. Immune-related gene and immunohistochemistry analyses showed that gram-negative bacteria load inversely correlated with M2 macrophages. F. nucleatum-associated OSCC has a specific immune microenvironment, is more frequent in older, non-drinking patients, and associated with a favorable prognosis.
Immunotherapy has made a breakthrough in medical oncology with the approval of several immune checkpoint inhibitors in clinical routine, improving overall survival of advanced cancer patients with ...refractory disease. However only a minority of patients experience a durable response with these agents, which has led to the development of combination strategies and novel immunotherapy drugs to further counteract tumor immune escape. Epigenetic regulations can be altered in oncogenesis, favoring tumor progression. The development of epidrugs has allowed targeting successfully these altered epigenetic patterns in lymphoma and leukemia patients. It has been recently shown that epigenetic alterations can also play a key role in tumor immune escape. Epidrugs, like HDAC inhibitors, can prime the anti-tumor immune response, therefore constituting interesting partners to develop combination strategies with immunotherapy agents. In this review, we will discuss epigenetic regulations involved in oncogenesis and immune escape and describe the clinical development of combining HDAC inhibitors with immunotherapies.
Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor (EGFR) in combination with platinum-based chemotherapy has been for the decade standard of care for the treatment of ...head and neck squamous cell carcinomas (HNSCC) patients in the first-line recurrent and/or metastatic setting. The KEYNOTE-048 trial published last year established a new paradigm in this setting with the demonstration that immunotherapy should be given either alone or in combination with chemotherapy. Indeed, pembrolizumab, an antiprogrammed cell death 1 (PD-1) immune checkpoint inhibitor, improved overall survival as compared to the EXTREME regimen in patients expressing PD-L1 in the tumor microenvironment, which represents a large majority of the patient population. In this review, we will decipher this important change of paradigm in the first-line treatment of recurrent and/or metastatic HNSCC, and discuss associated challenges.
Monalizumab is a monoclonal antibody targeting the inhibitory natural killer group 2A (NKG2A) receptor localised on natural killer (NK) and T cells. Its ligand, the human leukocyte antigen E (HLA-E), ...is overexpressed in squamous cell carcinoma of the head and neck (SCCHN). By targeting the HLA-E-NKG2A pathway, monalizumab may enhance NK and T cell activity.
The UPSTREAM trial is a biomarker-driven umbrella trial studying targeted therapies and immunotherapies in patients with recurrent/metastatic (R/M) SCCHN progressing after platinum therapy. The immunotherapy 1 (I1) cohort was a phase II, single-arm substudy evaluating monalizumab (10 mg/kg intravenously on day 1 of a 14-day cycle). The primary end-point was the objective response (OR) rate (Response Evaluation Criteria in Solid Tumours 1.1) over the first 16 weeks. A two-stage Simon design was used (H1 15%, H0 3%, α 8%, power 90%) with pre-planned interruption of accrual if no OR was observed after the first 25 patients.
Twenty-six eligible patients were enrolled. Seventeen (65%) patients had received ≥2 previous lines of systemic treatment, and 15 (58%) patients were PD(-L)1 inhibitor pretreated. No OR was observed. Stable disease was observed in 6 patients (23%) with a median duration of 3.8 months (95% confidence interval CI: 2.7–NE). The median progression-free survival and overall survival were 1.7 months (95% CI: 1.5–1.8) and 6.7 months (95% CI: 3.0–9.6), respectively. The most frequent treatment-related adverse event was grade I/II fatigue (19%).
Monalizumab monotherapy has limited activity in R/M SCCHN. The I1 cohort did not meet its primary objective. Monalizumab combined with durvalumab is under investigation within UPSTREAM.
•This study demonstrates the feasibility of UPSTREAM, a biomarker-driven trial for SCCHN.•This is the first trial of monalizumab monotherapy in SCCHN.•Disease stabilization was observed in 23% of the patients.•Patients previously exposed to PD-(L)1 inhibitors had a higher median OS.
Hyperprogressive disease (HPD) is a recently acknowledged pattern of rapid tumor progression after the initiation of immune checkpoint inhibitors. HPD has been observed across various types of tumors ...and has been associated with poor survival. We performed a meta-analysis to identify baseline (i.e., prior to programmed cell death 1 PD-1, PDCD1 / programmed cell death 1 ligand 1 PD-L1, CD274 inhibitor therapy) patient factors associated with risks of developing HPD during PD-1/PD-L1 inhibitor therapy. We searched eight databases until 6 June 2019. We calculated the summary odds ratio (OR) and its 95% confidence interval (CI) using the random-effects model and explored between-study heterogeneity and small-study effects. A total of nine articles was eligible (217 HPD cases, 1519 cancer patients) for meta-analysis. There was no standard definition of HPD, and the incidence of HPD ranged from 1 to 30%. We identified twenty-three baseline patient factors, of which five factors were statistically significantly associated with HPD. These were serum lactate dehydrogenase (LDH) above the upper normal limit (OR = 1.89, 95% CI = 1.02-3.49,
= 0.043), more than two metastatic sites (OR = 1.86, 1.34-2.57,
< 0.001), liver metastases (OR = 3.33, 2.07-5.34,
< 0.001), Royal Marsden Hospital prognostic score of 2 or above (OR = 3.33, 1.96-5.66,
< 0.001), and positive PD-L1 expression status that was inversely correlated with HPD (OR = 0.60, 0.36-0.99,
= 0.044). Between-study heterogeneity was low. Evidence of small-study effect was found in one association (PD-L1 expression). Subset analyses of patients with non-small cell lung cancer showed similar results. Future studies are warranted to identify underlying molecular mechanisms and to test their roles as predictive biomarkers of HPD.
Although immune checkpoint inhibitors have shown improvement in survival in comparison to chemotherapy in urothelial bladder cancer, many patients still fail to respond to these treatments and actual ...efforts are made to identify predictive factors of response to immunotherapy. Understanding the tumor-intrinsic molecular basis, like oncogenic pathways conditioning the presence or absence of tumor-infiltrating T cells (TILs), should provide a new rationale for improved anti-tumor immune therapies.
In this study, we found that urothelial bladder cancer from human samples bearing PIK3CA gene mutations was significantly associated with lower expression of a defined immune gene signature, compared to unmutated ones. We identified a reduced 10-gene immune gene signature that discriminates muscle-invasive bladder cancer (MIBC) samples according to immune infiltration and PIK3CA mutation. Using a humanized mouse model, we observed that BKM120, a pan-PI3K inhibitor, significantly inhibited the growth of a human bladder cancer cell line bearing a PIK3CA mutation, associated to increased immune cell infiltration (hCD45+). Using qRT-PCR, we also found an increase in the expression of chemokines and immune genes in PIK3CA-mutated tumors from mice treated with BKM120, reflecting an active immune infiltrate in comparison to untreated ones. Moreover, the addition of BKM120 rendered PIK3CA-mutated tumors sensitive to PD-1 blockade. Our results provide a relevant rationale for combination strategies of PI3K inhibitors with immune checkpoint inhibitors to overcome resistance to immune checkpoint inhibitors.