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Table of Contents
EDITORIAL
Year : 2019  |  Volume : 2  |  Issue : 2  |  Page : 224-225

Beyond the tumor and tumor milieu - Factors affecting responses to immunotherapy


Department of Medical Oncology, Kovai Medical Center and Hospital, Coimbatore, Tamil Nadu, India

Date of Web Publication20-Dec-2019

Correspondence Address:
Ram K Abhinav
Department of Medical Oncology, Kovai Medical Center and Hospital, Avinashi Road, Coimbatore - 641 014, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/CRST.CRST_105_19

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How to cite this article:
Rangarajan B, Abhinav RK. Beyond the tumor and tumor milieu - Factors affecting responses to immunotherapy. Cancer Res Stat Treat 2019;2:224-5

How to cite this URL:
Rangarajan B, Abhinav RK. Beyond the tumor and tumor milieu - Factors affecting responses to immunotherapy. Cancer Res Stat Treat [serial online] 2019 [cited 2020 Feb 22];2:224-5. Available from: http://www.crstonline.com/text.asp?2019/2/2/224/273669



Immune checkpoint inhibitors have made inroads in the treatment of numerous malignancies. Most of the clinical trials use biomarkers such as programmed death-ligand 1 (PD-L1) expression, microsatellite instability (MSI), and tumor mutational burden (TMB) as predictive factors for response to immunotherapy drugs.[1] In spite of enthusiasm generated from the long-term 'durable responses' seen in approximately 15%–20% of patients across all cancer types, immunotherapy has failed to achieve the goal of stimulating a lasting antitumor immune response in a majority of patients. We need biomarkers to not only predict responses but also to evaluate multiple host and tumor factors which will help in selecting patients who will benefit from enhanced antitumor immune stimulation which should ultimately enable more patients to benefit from these agents. One of the burning questions which remains unaddressed is whether steroids can abrogate the beneficial effects of immunotherapies. Many of the patients are on steroids for a variety of reasons which may include bone pain, supportive care, dyspnea, other concomitant diseases, and most importantly immune-related adverse events (IrAEs). However, patients receiving steroids before enrollment/randomization have been routinely excluded from immunotherapy clinical trials.

Immunotherapy drugs are believed to reawaken the cell-mediated immunity and thus require an intact and functioning immune system. Steroids, in turn, are known to be immunosuppressive by impairing the T-lymphocyte activation.[2] However, the jury is still out on whether steroids decrease the efficacy of checkpoint inhibitors, with some studies reporting a decreased progression-free survival and overall survival (OS)[3],[4] and others reporting no difference in outcomes.[5]

The present study in this issue of the journal consists of real-world data analyzing the effect of steroids on efficacy of checkpoint inhibitors. The authors have retrospectively analyzed data of 155 patients treated with immunotherapy, 38 of whom have received steroids (>10 mg prednisolone equivalent) along with checkpoint inhibitors.[6] It is interesting to note that steroids were administered only in 12 patients (7.7%) for IrAEs while 26 patients (16.77%) received steroids for other reasons including palliation. The real-world usage of steroids for non-IrAE may be reflected in these numbers with many patients who may require steroids while on immunotherapy which may not be reflected in clinical trials due to inherent selection bias while planning exclusion criteria. The retrospective series shows no significant detriment due to steroid usage irrespective of indication which is heartening. However, the study shows a signal of detriment for the usage of steroids of <10-day duration, and the authors surmise that longer duration of steroids may be for more definite indications such as IrAE or preexisting autoimmune comorbid status while shorter duration may have been unindicated usage. The numbers in this study, however, are too small to draw such a conclusion. Similarly, 27 of the 38 patients who received steroids also received concurrent antibiotics and had significantly poorer median OS. This could well be due to poorer performance status and infection-associated morbidities rather than effect of antibiotics. Confounding factors affecting OS need to be remembered, especially when one takes into account that this cohort included patients with recurrent cancers, especially oral cavity cancers with all the attendant problems of poor nutrition, fungation, ulceration, and susceptibility to severe secondary infections.

Unlike the previous studies, the present study includes a variety of cancers with lung and head-and-neck cancers forming majority of the cases. Further subcategorization with respect to individual cancer site might project data for only a very small number of patients in each category. Although the study shows no difference in outcomes between the two groups, it is a combined analysis of different cancer types, with difference in lines of therapy, prior therapy, PD-L1 expression, and burden of disease. An analysis of such data could preclude any definitive conclusion since only 38 patients received steroids. Certain biomarkers are reported to predict for poor outcomes in patients receiving steroids. The increment of neutrophil/leukocyte–lymphocyte ratio and absolute neutrophil count after steroids has been shown to be a negative prognostic marker in breast and prostate cancers.[7],[8] The study by Fucà et al. showed that the neutrophil/leukocyte–lymphocyte ratio, derived neutrophil/leukocyte–lymphocyte ratio, and relative eosinophil count could act as prognostic markers.[5] The present study also reports the negative impact of the use of antibiotics. None of the prior studies have evaluated this correlation. This could probably be because the patients were sicker with severe infection which negatively impacted OS; nevertheless, this finding warrants further evaluation. Antibiotics themselves may alter the gut flora, and it is well recognized that gut microbiota may modulate the immune responses to checkpoint inhibitors.[9],[10]

The success of immune stimulation depends on many tumor factors such as the PD-L1 status, MSI, TMB, and neoantigen load and milieu-related factors, including tumor-infiltrating lymphocytes and regulatory T-cells. However, the total 'host environment' goes beyond the tumor and tumor milieu and may include the changes in this host environment secondary to concomitant medications including corticosteroids, gut microbiome, antibiotics, or use of proton pump inhibitors which may alter the gut microbiome, diet, nutritional status, and many other mutually dependent factors, some of which may not be identified at the present time. The literature on specific antibiotic classes that have differential effects in abrogation of immune response is unavailable at present. Future studies are required to investigate the effect of steroids and antibiotics on the clinical efficacy of checkpoint inhibitors while stratifying across different clinical and molecular subgroups. However, designing such studies may be challenging and fraught with design and ethical problems. The usage of steroids may be mandatory in many clinical situations, as is the use of antibiotics. The present study is important in that it once again reassures us that steroids if used appropriately may not abrogate responses to immunotherapy. The use of antibiotics similarly may be unavoidable in many clinical settings; however, the signal of detriment needs to be evaluated further. We must acknowledge that data regarding the use of steroids or antibiotics in the setting of immunotherapy may never be answered in a prospective or randomized fashion and such real-world reports will have to serve as the guide.



 
  References Top

1.
Hellmann MD, Nathanson T, Rizvi H, Creelan BC, Sanchez-Vega F, Ahuja A, et al. Genomic features of response to combination immunotherapy in patients with advanced non-small-cell lung cancer. Cancer Cell 2018;33:843-52.e4.  Back to cited text no. 1
    
2.
Mahata B, Zhang X, Kolodziejczyk AA, Proserpio V, Haim-Vilmovsky L, Taylor AE, et al. Single-cell RNA sequencing reveals T helper cells synthesizing steroids de novo to contribute to immune homeostasis. Cell Rep 2014;7:1130-42.  Back to cited text no. 2
    
3.
Arbour KC, Mezquita L, Long N, Rizvi H, Auclin E, Ni A, et al. Impact of baseline steroids on efficacy of programmed cell death-1 and programmed death-ligand 1 blockade in patients with non-small-cell lung cancer. J Clin Oncol 2018;36:2872-8.  Back to cited text no. 3
    
4.
Scott SC, Pennell NA. Early use of systemic corticosteroids in patients with advanced NSCLC treated with nivolumab. J Thorac Oncol 2018;13:1771-5.  Back to cited text no. 4
    
5.
Fucà G, Galli G, Poggi M, Lo Russo G, Proto C, Imbimbo M, et al. Modulation of peripheral blood immune cells by early use of steroids and its association with clinical outcomes in patients with metastatic non-small cell lung cancer treated with immune checkpoint inhibitors. ESMO Open 2019;4:e000457.  Back to cited text no. 5
    
6.
Kapoor A, Noronha V, Patil VM, Joshi A, Menon N, Abraham G, et al. Concomitant use of corticosteroids and immune checkpoint inhibitors in patients with solid neoplasms: A real-world experience from a tertiary cancer center. Cancer Res Stat Treat 2019;2:204-8.  Back to cited text no. 6
  [Full text]  
7.
Mehra N, Sharp A, Lorente D, Dolling D, Sumanasuriya S, Johnson B, et al. Neutrophil to lymphocyte ratio in castration-resistant prostate cancer patients treated with daily oral corticosteroids. Clin Genitourin Cancer 2017;15:678-84.e1.  Back to cited text no. 7
    
8.
Orditura M, Galizia G, Diana A, Saccone C, Cobellis L, Ventriglia J, et al. Neutrophil to lymphocyte ratio (NLR) for prediction of distant metastasis-free survival (DMFS) in early breast cancer: A propensity score-matched analysis. ESMO Open 2016;1:e000038.  Back to cited text no. 8
    
9.
Panebianco C, Andriulli A, Pazienza V. Pharmacomicrobiomics: Exploiting the drug-microbiota interactions in anticancer therapies. Microbiome 2018;6:92.  Back to cited text no. 9
    
10.
Fessler J, Matson V, Gajewski TF. Exploring the emerging role of the microbiome in cancer immunotherapy. J Immunother Cancer 2019;7:108.  Back to cited text no. 10
    




 

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