Abstract
Adoptive cell therapy with tumor-infiltrating lymphocytes (TILs) was recently approved for patients with advanced melanoma (metastatic or unresectable) previously treated with immune checkpoint inhibitors and BRAF/MEK targeted therapies (where appropriate). Tumor-infiltrating lymphocytes isolated from patient-derived tumor tissues enter the tumor microenvironment and recognize tumor-specific antigens, leading to the destruction of tumor cells. The multistep TIL cell therapy journey is led by a multidisciplinary health care team. Patients selected for TIL cell therapy undergo tumor tissue procurement for TIL generation, followed by preparative lymphodepletion before receiving a single-dose infusion of TIL and a short course of high-dose interleukin-2. Successful implementation of TIL cell therapy requires well-established procedures and workflows to select and screen patients, procure tumor tissue, administer TIL cell therapy, and monitor patients during treatment and after discharge. The advanced practice provider plays a central role in a patient’s TIL treatment journey by planning and coordinating care across the health-care system, educating patients and staff, and providing direct and supportive patient care. Here, we review the treatment landscape for advanced melanoma and clinical data supporting TIL cell therapy. We also provide guidance related to patient selection, tumor tissue procurement, TIL cell therapy regimen, safety monitoring, symptom management, and post-discharge follow-up.
References
American Cancer Society. (2023). Melanoma skin cancer stages. https://www.cancer.org/cancer/types/melanoma-skin-cancer/detection-diagnosis-staging/melanoma-skin-cancer-stages.html
Antohe, M., Nedelcu, R. I., Nichita, L., Popp, C. G., Cioplea, M., Brinzea, A.,...Turcu, G. (2019). Tumor infiltrating lymphocytes: The regulator of melanoma evolution. Oncology Letters, 17(5), 4155–4161. https://doi.org/10.3892/ol.2019.9940
Array BioPharma Inc. (2018). Mektovi (binimetinib) package insert. Boulder, CO, USA: Array BioPharma Inc. https://labeling.pfizer.com/ShowLabeling.aspx?id=12988
Array BioPharma Inc. (2020). Braftovi (encorafenib) package insert. Boulder, CO, USA: Array BioPharma Inc. https://labeling.pfizer.com/ShowLabeling.aspx?id=12988
Ascierto, P. A., Dréno, B., Larkin, J., Ribas, A., Liszkay, G., Maio, M.,...McArthur, G. A. (2021). 5-year outcomes with cobimetinib plus vemurafenib in BRAFV600 mutation-positive advanced melanoma: Extended follow-up of the coBRIM study. Clinical Cancer Research, 27(19), 5225–5235. https://doi.org/10.1158/1078-0432.ccr-21-0809
Ascierto, P. A., Lipson, E. J., Dummer, R., Larkin, J., Long, G. V., Sanborn, R. E.,...Grob, J. J. (2023). Nivolumab and relatlimab in patients with advanced melanoma that had progressed on anti-programmed death-1/programmed death ligand 1 therapy: Results from the phase I/IIa RELATIVITY-020 trial. Journal of Clinical Oncology, 41(15), 2724–2735. https://doi.org/10.1200/jco.22.02072
Betof Warner, A., Corrie, P. G., & Hamid, O. (2023). Tumor-infiltrating lymphocyte therapy in melanoma: Facts to the future. Clinical Cancer Research, 29(10), 1835–1854. https://doi.org/10.1158/1078-0432.ccr-22-1922
Betof Warner, A., Hamid, O., Komanduri, K., Amaria, R., Butler, M. O., Haanen, J.,...Schoenfeld, A. J. (2024). Expert consensus guidelines on management and best practices for tumor-infiltrating lymphocyte cell therapy. Journal for Immunotherapy of Cancer, 12(2). https://doi.org/10.1136/jitc-2023-008735
Bhattacharya, S., Goyal, A., Kaur, P., Singh, R., & Kalra, S. (2020). Anticancer drug-induced thyroid dysfunction. European Endocrinology, 16(1), 32–39. https://doi.org/10.17925/ee.2020.16.1.32
Bristol-Myers Squibb. (2022). Opdualag (nivolumab and relatlimab-rmbw) package insert. Princeton, NJ, USA: Bristol-Myers Squibb. https://packageinserts.bms.com/pi/pi_opdualag.pdf
Bristol-Myers Squibb. (2023). Yervoy (ipilimumab) package insert. Princeton, NJ, USA: Bristol-Myers Squibb. http://packageinserts.bms.com/pi/pi_yervoy.pdf
Bristol-Myers Squibb Company. (2023). Opdivo (nivolumab) package insert. Princeton, NJ, USA: Bristol-Myers Squibb Company. https://packageinserts.bms.com/pi/pi_opdivo.pdf
Chapman, P. B., Jayaprakasam, V. S., Panageas, K. S., Callahan, M., Postow, M. A., Shoushtari, A. N.,...Betof Warner, A. (2021). Risks and benefits of reinduction ipilimumab/nivolumab in melanoma patients previously treated with ipilimumab/nivolumab. Journal for Immunotherapy of Cancer, 9(10). https://doi.org/10.1136/jitc-2021-003395
Cheng, L., Lopez-Beltran, A., Massari, F., MacLennan, G. T., & Montironi, R. (2018). Molecular testing for BRAF mutations to inform melanoma treatment decisions: A move toward precision medicine. Modern Pathology, 31(1), 24–38. https://doi.org/10.1038/modpathol.2017.104
Chesney, J., Lewis, K. D., Kluger, H., Hamid, O., Whitman, E., Thomas, S.,...Sarnaik, A. (2022). Efficacy and safety of lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, in patients with advanced melanoma after progression on immune checkpoint inhibitors and targeted therapies: Pooled analysis of consecutive cohorts of the C-144-01 study. Journal for Immunotherapy of Cancer, 10(12). https://doi.org/10.1136/jitc-2022-005755
Cheson, B. D., Vena, D. A., Foss, F. M., & Sorensen, J. M. (1994). Neurotoxicity of purine analogs: A review. Journal of Clinical Oncology, 12(10), 2216–2228. https://doi.org/10.1200/jco.1994.12.10.2216
Costa, A. L., Abreu, C., Pacheco, T. R., Macedo, D., Sousa, A. R., Pulido, C.,...Costa, L. (2015). Prevention of nausea and vomiting in patients undergoing oral anticancer therapies for solid tumors. BioMed Research International, 2015, 309601. https://doi.org/10.1155/2015/309601
Crompton, J. G., Klemen, N., & Kammula, U. S. (2018). Metastasectomy for tumor-infiltrating lymphocytes: An emerging operative indication in surgical oncology. Annals of Surgical Oncology, 25(2), 565–572. https://doi.org/10.1245/s10434-017-6266-8
De Risi, I., Sciacovelli, A. M., & Guida, M. (2022). Checkpoint inhibitors immunotherapy in metastatic melanoma: When to stop treatment? Biomedicines, 10(10), 2424. https://doi.org/10.3390/biomedicines10102424
Ding, X., Herzlich, A. A., Bishop, R., Tuo, J., & Chan, C. C. (2008). Ocular toxicity of fludarabine: A purine analog. Expert Review of Ophthalmology, 3(1), 97–109. https://doi.org/10.1586/17469899.3.1.97
Draghi, A., Borch, T. H., Radic, H. D., Chamberlain, C. A., Gokuldass, A., Svane, I. M., & Donia, M. (2019). Differential effects of corticosteroids and anti-TNF on tumor-specific immune responses: Implications for the management of irAEs. International Journal of Cancer, 145(5), 1408–1413. https://doi.org/10.1002/ijc.32080
Dudley, M. E., Wunderlich, J. R., Yang, J. C., Sherry, R. M., Topalian, S. L., Restifo, N. P.,...Rosenberg, S. A. (2005). Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. Journal of Clinical Oncology, 23(10), 2346–2357. https://doi.org/10.1200/jco.2005.00.240
Dummer, R., Flaherty, K. T., Robert, C., Arance, A., de Groot, J. W. B., Garbe, C.,...Ascierto, P. A. (2022). COLUMBUS 5-year update: A randomized, open-label, phase III trial of encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF V600-mutant melanoma. Journal of Clinical Oncology, 40(36), 4178–4188. https://doi.org/10.1200/jco.21.02659
Dutcher, J. P., Schwartzentruber, D. J., Kaufman, H. L., Agarwala, S. S., Tarhini, A. A., Lowder, J. N., & Atkins, M. B. (2014). High dose interleukin-2 (Aldesleukin) - expert consensus on best management practices-2014. Journal for Immunotherapy of Cancer, 2(1), 26. https://doi.org/10.1186/s40425-014-0026-0
Gastman, B., Agarwal, P. K., Berger, A., Boland, G., Broderick, S., Butterfield, L. H.,...Kaufman, H. L. (2020). Defining best practices for tissue procurement in immuno-oncology clinical trials: Consensus statement from the Society for Immunotherapy of Cancer Surgery Committee. Journal for Immunotherapy of Cancer, 8(2). https://doi.org/10.1136/jitc-2020-001583
Genentech USA. (2020). Zelboraf (vemurafenib) package insert. South San Francisco, CA, USA: Genentech USA. https://www.gene.com/download/pdf/zelboraf_prescribing.pdf
Genentech USA, Inc. (2023). Cotellic (cobimetinib) package insert. South San Francisco, CA, USA: Genentech USA, Inc. https://www.gene.com/download/pdf/cotellic_prescribing.pdf
Goff, S. L., Dudley, M. E., Citrin, D. E., Somerville, R. P., Wunderlich, J. R., Danforth, D. N.,...Rosenberg, S. A. (2016). Randomized, prospective evaluation comparing intensity of lymphodepletion before adoptive transfer of tumor-infiltrating lymphocytes for patients with metastatic melanoma. Journal of Clinical Oncology, 34(20), 2389–2397. https://doi.org/10.1200/jco.2016.66.7220
Goff, S. L., & Rosenberg, S. A. (2019). BRAF inhibition: Bridge or boost to T-cell therapy? Clinical Cancer Research, 25(9), 2682–2684. https://doi.org/10.1158/1078-0432.ccr-19-0286
Hassel, J. C., Sarnaik, A., Chesney, J., Medina, T., Hamid, O., Thomas, S.,...Kluger, H. (2022). Number of IL-2 doses and clinical outcomes of tumor-infiltrating lymphocyte (TIL) cell therapy: Post hoc analysis of the C-144-01 trial of lifileucel in patients with advanced melanoma [abstract 35MO]. Immuno-Oncology and Technology, 16(suppl 1), 100140. https://doi.org/10.1016/j.iotech.2022.100140
Hopewell, E. L., Cox, C., Pilon-Thomas, S., & Kelley, L. L. (2019). Tumor-infiltrating lymphocytes: Streamlining a complex manufacturing process. Cytotherapy, 21(3), 307–314. https://doi.org/10.1016/j.jcyt.2018.11.004
Iovance Biotherapeutics. (2024). Amtagvi (lifileucel) package insert. Philadelphia, PA: Iovance Biotherapeutics. https://www.iovance.com/AMTAGVI_USPI
Jain, M., & Wylie, W. P. (2024). Diphenoxylate and atropine. In StatPearls. StatPearls Publishing.
Kalantari, K., Chang, J. N., Ronco, C., & Rosner, M. H. (2013). Assessment of intravascular volume status and volume responsiveness in critically ill patients. Kidney International, 83(6), 1017–1028. https://doi.org/10.1038/ki.2012.424
Kaplan, J. E., Benson, C., Holmes, K. K., Brooks, J. T., Pau, A., & Masur, H. (2009). Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: Recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. Morbidity and Mortality Weekly Report: Recommendations and Reports, 58(Rr-4), 1–207.
Kazemi, M. H., Sadri, M., Najafi, A., Rahimi, A., Baghernejadan, Z., Khorramdelazad, H., & Falak, R. (2022). Tumor-infiltrating lymphocytes for treatment of solid tumors: It takes two to tango? Frontiers in Immunology, 13, 1018962. https://doi.org/10.3389/fimmu.2022.1018962
Kollerup Madsen, B., Hilscher, M., Zetner, D., & Rosenberg, J. (2018). Adverse reactions of dimethyl sulfoxide in humans: A systematic review. F1000Res, 7, 1746. https://doi.org/10.12688/f1000research.16642.2
Kumar, A., Watkins, R., & Vilgelm, A. E. (2021). Cell therapy with TILs: Training and taming T cells to fight cancer. Frontiers in Immunology, 12, 690499. https://doi.org/10.3389/fimmu.2021.690499
Kumar, H., Gupta, P. K., Mishra, D. K., Sarkar, R. S., & Jaiprakash, M. (2006). Leucodepletion and blood products. Medical Journal Armed Forces India, 62(2), 174–177. https://doi.org/10.1016/s0377-1237(06)80064-x
Kurlowicz, L., & Wallace, M. (1999). The Mini Mental State Examination (MMSE). Interprofessional Comprehensive Geriatric Toolkit. https://cgatoolkit.ca/Uploads/ContentDocuments/MMSE.pdf
Larkin, J., Sarnaik, A., Chesney, J. A., Khushalani, N. I., Kirkwood, J. M., Weber, J. S.,...Hamid, O. (2021). Lifileucel (LN-144), a cryopreserved autologous tumor infiltrating lymphocyte (TIL) therapy in patients with advanced melanoma: Evaluation of impact of prior anti-PD-1 therapy [abstract]. Journal of Clinical Oncology, 39(15 suppl), 9505. https://doi.org/10.1200/JCO.2021.39.15_suppl.9505
Lim, S. Y., Shklovskaya, E., Lee, J. H., Pedersen, B., Stewart, A., Ming, Z.,...Rizos, H. (2023). The molecular and functional landscape of resistance to immune checkpoint blockade in melanoma. Nature Communication, 14(1), 1516. https://doi.org/10.1038/s41467-023-36979-y
Lopes, J., Rodrigues, C. M. P., Gaspar, M. M., & Reis, C. P. (2022). Melanoma management: From epidemiology to treatment and latest advances. Cancers, 14(19). https://doi.org/10.3390/cancers14194652
McQuade, R. M., Stojanovska, V., Abalo, R., Bornstein, J. C., & Nurgali, K. (2016). Chemotherapy-induced constipation and diarrhea: Pathophysiology, current and emerging treatments. Frontiers in Pharmacology, 7, 414. https://doi.org/10.3389/fphar.2016.00414
Mehta, G. U., Malekzadeh, P., Shelton, T., White, D. E., Butman, J. A., Yang, J. C.,...Sherry, R. M. (2018). Outcomes of adoptive cell transfer with tumor-infiltrating lymphocytes for metastatic melanoma patients with and without brain metastases. Journal of Immunotherapy, 41(5), 241–247. https://doi.org/10.1097/cji.0000000000000223
Merck & Co., Inc. (2023). Keytruda (pembrolizumab) package insert. Rahway, NJ, USA: Merck & Co., Inc. https://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf
Moreno, S. E., Alves-Filho, J. C., Bertozi, G., Alfaya, T. M., Thèze, J., Ferreira, S. H., & Vargaftig, B. B. (2006). Systemic administration of interleukin-2 inhibits inflammatory neutrophil migration: Role of nitric oxide. British Journal of Pharmacology, 148(8), 1060–1066. https://doi.org/10.1038/sj.bjp.0706835
Mullinax, J. E., Egger, M. E., McCarter, M., Monk, B. J., Toloza, E. M., Brousseau, S.,...Sarnaik, A. (2022). Surgical considerations for tumor tissue procurement to obtain tumor-infiltrating lymphocytes for adoptive cell therapy. Cancer Journal, 28(4), 285–293. https://doi.org/10.1097/ppo.0000000000000608
National Cancer Institute. (2024). SEER Cancer Stat Facts: Melanoma of the Skin. https://seer.cancer.gov/statfacts/html/melan.html
National Institutes of Health. (2017). Cyclophosphamide. In LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. National Institutes of Health.
Novartis Pharmaceuticals. (2022). Tafinlar (dabrafenib) package insert. East Hanover, NJ, USA: Novartis Pharmaceuticals. https://www.novartis.com/us-en/sites/novartis_us/files/tafinlar.pdf
Novartis Pharmaceuticals Corporation. (2022). Mekinist (trametinib) package insert. East Hanover, NJ, USA: Novartis Pharmaceuticals Corporation. https://www.novartis.com/us-en/sites/novartis_us/files/mekinist.pdf
Olson, D. J., Eroglu, Z., Brockstein, B., Poklepovic, A. S., Bajaj, M., Babu, S.,...Luke, J. J. (2021). Pembrolizumab plus ipilimumab following anti-PD-1/L1 failure in melanoma. Journal of Clinical Oncology, 39(24), 2647–2655. https://doi.org/10.1200/jco.21.00079
Pachella, L. A., Madsen, L. T., & Dains, J. E. (2015). The toxicity and benefit of various dosing strategies for interleukin-2 in metastatic melanoma and renal cell carcinoma. Journal of the Advanced Practitioner in Oncology, 6(3), 212–221. https://doi.org/10.6004/jadpro.2015.6.3.3
Paydas, S., Ozonur, H., Paydas, S., Kaya, B., & Efe, C. (2021). The assessment of volume status with body composition monitor in cancer patients. Eurasian Journal of Medical Investigation, 5(2), 246–250. https://doi.org/10.14744/ejmi.2021.40162
Pires da Silva, I., Ahmed, T., Reijers, I. L. M., Weppler, A. M., Betof Warner, A., Patrinely, J. R.,...Long, G. V. (2021). Ipilimumab alone or ipilimumab plus anti-PD-1 therapy in patients with metastatic melanoma resistant to anti-PD-(L)1 monotherapy: A multicentre, retrospective, cohort study. Lancet Oncology, 22(6), 836–847. https://doi.org/10.1016/s1470-2045(21)00097-8
Reddy, V., & Winston, N. R. (2023). Mesna. In StatPearls. StatPearls Publishing LLC.
Robert, C., Grob, J. J., Stroyakovskiy, D., Karaszewska, B., Hauschild, A., Levchenko, E.,...Long, G. V. (2019b). Five-year outcomes with dabrafenib plus trametinib in metastatic melanoma. New England Journal of Medicine, 381(7), 626–636. https://doi.org/10.1056/NEJMoa1904059
Robert, C., Ribas, A., Schachter, J., Arance, A., Grob, J. J., Mortier, L.,...Long, G. V. (2019a). Pembrolizumab versus ipilimumab in advanced melanoma (KEYNOTE-006): Post-hoc 5-year results from an open-label, multicentre, randomised, controlled, phase 3 study. Lancet Oncology, 20(9), 1239–1251. https://doi.org/10.1016/s1470-2045(19)30388-2
Rogers, M., McKenzie, G., Rattani, A., Yusuf, M., Chesney, J. A., & Dunlap, N. E. (2023). Tolerability and response of palliative radiotherapy in patients receiving tumor-infiltrating lymphocyte therapy [abstract]. Journal of Clinical Oncology, 41(16 suppl), e14527. https://doi.org/10.1200/JCO.2023.41.16_suppl.e14527
Rohaan, M. W., Borch, T. H., van den Berg, J. H., Met, Ö., Kessels, R., Geukes Foppen, M. H.,...Haanen, J. (2022). Tumor-infiltrating lymphocyte therapy or ipilimumab in advanced melanoma. New England Journal of Medicine, 387(23), 2113–2125. https://doi.org/10.1056/NEJMoa2210233
Rosenberg, S. A., Packard, B. S., Aebersold, P. M., Solomon, D., Topalian, S. L., Toy, S. T.,...White, D. (1988). Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. A preliminary report. New England Journal of Medicine, 319(25), 1676–1680. https://doi.org/10.1056/nejm198812223192527
Rosenberg, S. A., Yang, J. C., Sherry, R. M., Kammula, U. S., Hughes, M. S., Phan, G. Q.,...Dudley, M. E. (2011). Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clinical Cancer Research, 17(13), 4550–4557. https://doi.org/10.1158/1078-0432.ccr-11-0116
Rosenberg, S. A., Yannelli, J. R., Yang, J. C., Topalian, S. L., Schwartzentruber, D. J., Weber, J. S.,...White, D. E. (1994). Treatment of patients with metastatic melanoma with autologous tumor-infiltrating lymphocytes and interleukin 2. Journal of the National Cancer Institute, 86(15), 1159–1166. https://doi.org/10.1093/jnci/86.15.1159
Sarnaik, A. A., Hamid, O., Khushalani, N. I., Lewis, K. D., Medina, T., Kluger, H. M.,...Chesney, J. A. (2021). Lifileucel, a tumor-infiltrating lymphocyte therapy, in metastatic melanoma. Journal of Clinical Oncology, 39(24), 2656–2666. https://doi.org/10.1200/jco.21.00612
Savoia, P., Zavattaro, E., & Cremona, O. (2020). Clinical implications of acquired BRAF inhibitors resistance in melanoma. International Journal of Molecular Sciences, 21(24). https://doi.org/10.3390/ijms21249730
Schwartzentruber, D. J. (2001). Guidelines for the safe administration of high-dose interleukin-2. Journal of Immunotherapy, 24(4), 287–293. https://doi.org/10.1097/00002371-200107000-00004
Seth, R., Agarwala, S. S., Messersmith, H., Alluri, K. C., Ascierto, P. A., Atkins, M. B.,...Weber, J. (2023). Systemic therapy for melanoma: ASCO guideline update. Journal of Clinical Oncology, 41(30), 4794-4820. https://doi.org/10.1200/jco.23.01136
Tawbi, H. A., Schadendorf, D., Lipson, E. J., Ascierto, P. A., Matamala, L., Castillo Gutiérrez, E.,...Long, G. V. (2022). Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma. New England Journal of Medicine, 386(1), 24–34. https://doi.org/10.1056/NEJMoa2109970
Topalian, S. L., Solomon, D., Avis, F. P., Chang, A. E., Freerksen, D. L., Linehan, W. M.,...Simon, P. (1988). Immunotherapy of patients with advanced cancer using tumor-infiltrating lymphocytes and recombinant interleukin-2: A pilot study. Journal of Clinical Oncology, 6(5), 839–853. https://doi.org/10.1200/jco.1988.6.5.839
Topp, B. G., Thiagarajan, K., De Alwis, D. P., Snyder, A., & Hellmann, M. D. (2021). Lesion-level heterogeneity of radiologic progression in patients treated with pembrolizumab. Annals of Oncology, 32(12), 1618–1625. https://doi.org/10.1016/j.annonc.2021.09.006
Tyre, C. C., & Quan, W. (2007). Nursing care of patients receiving high-dose, continuous-infusion interleukin-2 with pulse dose and famotidine. Clinical Journal of Oncology Nursing, 11(4), 513–519. https://doi.org/10.1188/07.cjon.513-519
VanderWalde, A., Bellasea, S. L., Kendra, K. L., Khushalani, N. I., Campbell, K. M., Scumpia, P. O.,...Ribas, A. (2023). Ipilimumab with or without nivolumab in PD-1 or PD-L1 blockade refractory metastatic melanoma: A randomized phase 2 trial. Nature Medicine, 29(9), 2278–2285. https://doi.org/10.1038/s41591-023-02498-y
Villani, A., Potestio, L., Fabbrocini, G., Troncone, G., Malapelle, U., & Scalvenzi, M. (2022). The treatment of advanced melanoma: Therapeutic update. International Journal of Molecular Sciences, 23(12). https://doi.org/10.3390/ijms23126388
Wolchok, J. D., Chiarion-Sileni, V., Gonzalez, R., Grob, J. J., Rutkowski, P., Lao, C. D.,...Hodi, F. S. (2022). Long-term outcomes with nivolumab plus ipilimumab or nivolumab alone versus ipilimumab in patients with advanced melanoma. Journal of Clinical Oncology, 40(2), 127–137. https://doi.org/10.1200/jco.21.02229
Zhao, Y., Deng, J., Rao, S., Guo, S., Shen, J., Du, F.,...Li, J. (2022). Tumor infiltrating lymphocyte (TIL) therapy for solid tumor treatment: Progressions and challenges. Cancers, 14(17). https://doi.org/10.3390/cancers14174160
