Skip to main content

Advertisement

SpringerLink
Log in

Immunotherapy of cancer in the era of checkpoint inhibitor

  • Review
  • Published:
Clinical & Experimental Metastasis Aims and scope Submit manuscript

Abstract

Application of immunotherapy has revolutionized treatment of number of malignancies. We present a review of immunotherapy approaches, early-phase data of number of new immunotherapeutic targets in melanoma, cutaneous squamous cell carcinoma, Merkel cell cancer, and non-small cell lung cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Curran MA, Montalvo W, Yagita H, Allison JP (2010) PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc Natl Acad Sci USA 107(9):4275–4280. https://doi.org/10.1073/pnas.0915174107

    Article  PubMed  PubMed Central  Google Scholar 

  2. Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD et al (2015) Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 373(1):23–34. https://doi.org/10.1056/NEJMoa1504030

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D et al (2015) Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med 372(21):2006–2017. https://doi.org/10.1056/NEJMoa1414428

    Article  PubMed  PubMed Central  Google Scholar 

  4. Hirano F, Kaneko K, Tamura H, Dong H, Wang S, Ichikawa M et al (2005) Blockade of B7–H1 and PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity. Cancer Res 65(3):1089–1096

    CAS  PubMed  Google Scholar 

  5. Woo SR, Turnis ME, Goldberg MV, Bankoti J, Selby M, Nirschl CJ et al (2012) Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res 72(4):917–927. https://doi.org/10.1158/0008-5472.CAN-11-1620

    Article  CAS  PubMed  Google Scholar 

  6. Harding J, Patnaik A, Moreno V, Stein M, Jankowska A et al (2019) A phase Ia/Ib study of an anti-TIM-3 antibody (LY3321367) monotherapy or in combination with an anti-PD-L1 antibody (LY3300054): interim safety, efficacy, and pharmacokinetic finding in advanced cancers. J Clin Oncol 37(8):12–12. https://doi.org/10.1200/jco.2019.37.8_suppl.12

    Article  Google Scholar 

  7. Eastgate M, Atkinson A, Khattak A, Roy A, Haydon A et al (2018) Pushing the accelerator and releasing the brake: a phase I dose escalation study evaluating a LAG-3 fusion protein (eftilagimod alpha), together with pembrolizumab in unresectable or metastatic melanoma. J Clin Oncol. https://doi.org/10.1200/JCO.2018.36.15_suppl.e15099

    Article  Google Scholar 

  8. Hong S, Schoffski P, Calvo A, Sarantopoulos J, Olza M et al (2018) Phase I/II study of LAG525+/_spartalizumab (PDR001) in patients (pts) with advanced malignancies. J Clin Oncol 36(15_suppl):3012–3012. https://doi.org/10.1200/JCO.2018.36.15_suppl.3012

    Article  Google Scholar 

  9. Massarelli E (2016) Clinical safety and efficacy assessment of the CD137 agonist urelumab alone and in combination with nivolumab in patients with hematologic and solid tumor malignancies. J ImmunoTher Cancer 4(Suppl 1):172

    Google Scholar 

  10. Segal N, Logan T, Hodi S, McDermott D et al (2017) Results from an integrated safety analysis of urelumab, an agonist anti-CD137 monoclonal antibody. Clin Cancer Res 23(8):1929–36. https://doi.org/10.1158/1078-0432.CCR-16-1272

    Article  CAS  PubMed  Google Scholar 

  11. Segal N, He A, Doi T, Levy R, Bhatia S et al (2018) Phase I study of signle-agnet utomilumab (PF-05082566) a 4-1BB/CD137 agonist, in patients with advanced cancer. Clin Cancer Res 24(8):1816–23. https://doi.org/10.1158/1078-0432.CCR-17-1922

    Article  CAS  PubMed  Google Scholar 

  12. Tran B, Carvajal R, Marabelle A, Patel S, LoRusso P et al (2018) Dose escalation results from a first-in-human, phase I study of glucocorticoid-induced TNF receptor-related protein agonist AMG 228 in patients with advanced solid tumors. J ImmunoTher Cancer. https://doi.org/10.1186/s40425-018-0407-x

    Article  PubMed  PubMed Central  Google Scholar 

  13. Schumacher TN, Schreiber RD (2015) Neoantigens in cancer immunotherapy. Science 348(6230):69–74. https://doi.org/10.1126/science.aaa4971

    Article  CAS  PubMed  Google Scholar 

  14. Tran E, Turcotte S, Gros A, Robbins PF, Lu YC, Dudley ME et al (2014) Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Science 344(6184):641–645. https://doi.org/10.1126/science.1251102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. van Rooij N, van Buuren MM, Philips D, Velds A, Toebes M, Heemskerk B et al (2013) Tumor exome analysis reveals neoantigen-specific T-cell reactivity in an ipilimumab-responsive melanoma. J Clin Oncol 31(32):e439–e442. https://doi.org/10.1200/JCO.2012.47.7521

    Article  PubMed  Google Scholar 

  16. Ott P, Govindan R, Naing A, Friedlander T, Margolin K et al (2018) A personal neoantigen vaccine, NEO-PV-01, with anti-PD1 induces broad de novo anti-tumor immunity in patients with metastatic melanoma, NSCLC and bladder cancer. Cancer Res. https://doi.org/10.1158/1538-7445.AM2018-CT125

    Article  Google Scholar 

  17. Milhem M, Gonzales T, Median T, Kirkwood J, Buchbinder E, Mehmi I et al (2018) Intratumoral toll-like receptor 9 (TLR9) agonist, CmP-001, in combination with pembrolizumab can reverse resistance to PD-1 inhibition in a phase Ib trial in subjects with advanced melanoma. Cancer Res. https://doi.org/10.1158/1538-7445.AM2018-CT144

    Article  Google Scholar 

  18. Milhem M, Long G, Hoimes C, Amin A, Lao C et al (2019) Phase 1b/2, open label, multicenter, study of the combination of SD-101 and pembrolizumab in patients with advanced melanoma who are naïve to anti-PD-1 therapy. J Clin Oncol 37(15_suppl):9534. https://doi.org/10.1200/JCO.2019.37.15_suppl.9534

    Article  Google Scholar 

  19. Diab A, Haymaker C, Bernatchez C et al (2018) Intratumoral (IT) Injection of the TLR9 agonist tilsotolimod (IMO-2125) in combination with ipilimumab (ipi) triggers durable responses in PD-1 inhibitor refractory metastatic melanoma (rMM): results from a multicenter, phase I/II study. Ann Oncol. https://doi.org/10.1093/annonc/mdy289.001

    Article  Google Scholar 

  20. Thakur A, Huang M, Lum L (2018) Bispecific antibody based therapeutics: strengths and challenges. Blood Rev 32:339–347. https://doi.org/10.1016/j.blre.2018.02.004

    Article  CAS  PubMed  Google Scholar 

  21. Damato B, Dukes J, Goodal H, Carvajal R (2019) Teventafusp: T cell redirection for the treatment of metastatic uveal melanoma. Cancers. https://doi.org/10.3390/cancers11070971

    Article  PubMed  PubMed Central  Google Scholar 

  22. Piperno-Neumann S, Hassel J, Rukowski P et al (2021) Phase 3 randomized trial comparing tebentafusp with investigator’s choice in first line metastatic uveal melanoma. In: American Association for Cancer Research annual meeting 2021 abstract CT002.

  23. Boussiotis VA, Barber DL, Nakarai T, Freeman GJ, Gribben JG, Bernstein GM et al (1994) Prevention of T cell anergy by signaling through the gamma c chain of the IL-2 receptor. Science 266(5187):1039–1042

    Article  CAS  PubMed  Google Scholar 

  24. Naing A, Papadopoulos KP, Autio KA, Ott PA, Patel MR, Wong DJ et al (2016) Safety, antitumor activity, and immune activation of pegylated recombinant human interleukin-10 (AM0010) in patients with advanced solid tumors. J Clin Oncol 34(29):3562–3569. https://doi.org/10.1200/JCO.2016.68.1106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Hodi FS, Lee S, McDermott DF, Rao UN, Butterfield LH, Tarhini AA et al (2014) Ipilimumab plus sargramostim vs ipilimumab alone for treatment of metastatic melanoma: a randomized clinical trial. JAMA 312(17):1744–1753. https://doi.org/10.1001/jama.2014.13943

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Luke JJ, Donahue H, Nishino M, Giobbie-Hurder A, Davis M, Bailey N et al (2015) Single institution experience of ipilimumab 3 mg/kg with sargramostim (GM-CSF) in metastatic melanoma. Cancer Immunol Res 3(9):986–991. https://doi.org/10.1158/2326-6066.CIR-15-0066

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Davar D, Wang H, Chauvin J, Pagliano O, Fourcade J et al (2018) Phase Ib/II study of pembrolizumab and peglylated-interferon alfa-2b in advanced melanoma. J Clin Oncol 36(35):3450–3458. https://doi.org/10.1200/jco.18.00632

    Article  CAS  PubMed Central  Google Scholar 

  28. Grzywa T, Sosnowska A, Matryba P et al (2020) Myeloid cell-derived arginase in cancer immune response. Front Immunol 11:938. https://doi.org/10.3389/fimmu.2020.00938

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Sarnaik A, Khushalani N, Chesney J, Kluger H, Curti B et al (2019) Safety and efficacy of cryopreserved autologous tumor infiltrating lymphocyte therapy (LN-144, lifileucel) in advanced metastatic melanoma patients who progressed on multiple prior therapies including anti-PD-1. J Clin Oncol 37(15):2518–2518. https://doi.org/10.1200/JCO.2019.37.15_suppl.2518

    Article  Google Scholar 

  30. Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ et al (2014) Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med 371(16):1507–1517. https://doi.org/10.1056/NEJMoa1407222

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Morgan RA, Chinnasamy N, Abate-Daga D, Gros A, Robbins PF, Zheng Z et al (2013) Cancer regression and neurological toxicity following anti-MAGE-A3 TCR gene therapy. J Immunother 36(2):133–151. https://doi.org/10.1097/CJI.0b013e3182829903

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Robbins PF, Morgan RA, Feldman SA, Yang JC, Sherry RM, Dudley ME et al (2011) Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J Clin Oncol 29(7):917–924. https://doi.org/10.1200/JCO.2010.32.2537

    Article  PubMed  PubMed Central  Google Scholar 

  33. Migden MR, Rischin D, Schmults CD et al (2018) PD-1 blockade with cemiplimab in advanced cutaneous squamous-cell carcinoma. N Engl J Med 379:341–51. https://doi.org/10.1056/NEJMoa1805131

    Article  CAS  PubMed  Google Scholar 

  34. Hall ET, Fernandez-Lopez E, Silk AW et al (2020) Immunologic characteristics of nonmelanoma skin cancer: implications for immunotherapy. In: American Society of Clinical Oncology Educational Book 40 (March 24, 2020), pp 398–407. https://doi.org/10.1200/EDBK_278953

  35. Kaufman HL, Russell J, Hamid O et al (2016) Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, openlabel, phase 2 trial. Lancet Oncol 17:1374–1385

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kaufman HL, Russell JS, Hamid O et al (2018) Updated efficacy of avelumab in patients with previously treated metastatic Merkel cell carcinoma after _1 year of followup: JAVELIN Merkel 200, a phase 2 clinical trial. J Immunother Cancer 6:7

    Article  PubMed  PubMed Central  Google Scholar 

  37. Nghiem P, Bhatia S, Lipson EJ et al (2019) Durable tumor regression and overall survival in patients with advanced Merkel cell carcinoma receiving pembrolizumab as first-line therapy. J Clin Oncol 37:693–702

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. D’Angelo SP, Russell J, Lebbé C et al (2018) Efficacy and safety of first-line avelumab treatment in patients with stage IV metastatic Merkel cell carcinoma: a preplanned interim analysis of a clinical trial. JAMA Oncol 4:e180077

    Article  PubMed  PubMed Central  Google Scholar 

  39. West H, McCleod M, Hussein M, Morabito A, Rittmeyer A, Conter H et al (2019) Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (Impower130): a multicentre, randomized, open-label, phase 3 trial. Lancet Oncol 20:924–37. https://doi.org/10.1016/s1470-2045(19)30167-6137

    Article  CAS  PubMed  Google Scholar 

  40. Gandhi L, Rodriquez-Abreu D, Gadgeel S, Esteban E, Felip E et al (2018) Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med 378(22):2078–2092. https://doi.org/10.1056/NEJMoa1801005

    Article  CAS  PubMed  Google Scholar 

  41. Paz-Ares L, Luft A, Vicente D, Tafreshi A, Gumus M et al (2018) Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Engl J Med 379(21):2040–2051. https://doi.org/10.1056/nejmoa1810865

    Article  CAS  PubMed  Google Scholar 

  42. Reck M, Rodríguez-Abreu D, Robinson AG, KEYNOTE-024 Investigators et al (2016) Pembrolizumab versus chemotherapy for PD-L1–positive non-small-cell lung cancer. N Engl J Med 375(19):1823–1833. https://doi.org/10.1056/NEJMoa1606774

    Article  CAS  PubMed  Google Scholar 

  43. Mok TSK, Wu Y-L, Kudaba I, KEYNOTE-042 Investigators et al (2019) Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomized, open-label, controlled, phase 3 trial. Lancet 393(10183):1819–1830. https://doi.org/10.1016/S0140-6736(18)32409-7

    Article  CAS  PubMed  Google Scholar 

  44. Bodor JN, Bauman JR, Handorf EA et al (2020) Real-world progression-free survival in oncogenic driver-mutated non-small cell lung cancer treated with single-agent immunotherapy. In: 2020 North America Conference on Lung Cancer. Oral Abstract Session 2. Presented October 17, 2020

  45. Peters S, Ramalingam SS, Paz-Ares L et al (2019) Nivolumab + low-dose ipilimumab vs platinum-doublet chemotherapy as first-line treatment for advanced non-small cell lung cancer. In: 2019 ESMO Congress. Abstract LBA4. Presented September 28, 2019

  46. Hellmann MD, Paz-Ares L, Bernabe Caro R et al (2019) Nivolumab plus ipilimumab in advanced non-small cell lung cancer. N Engl J Med 381:2020–2031. https://doi.org/10.1056/NEJMoa1910231

    Article  CAS  PubMed  Google Scholar 

  47. Mehmi I, Brandao R, Hamid O, Ott P (2021) Cancer immunotherapy principles and practice, 2nd edn. Springer Publishing Company, New York. https://doi.org/10.1891/9781617052736.0024

    Book  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. The Angeles Clinic and Research Institute, Cedar Sinai Affiliate, Los Angeles, CA, USA

    Inderjit Mehmi & Omid Hamid

Authors
  1. Inderjit Mehmi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Omid Hamid
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Inderjit Mehmi.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Presented at the 8th International Cancer Metastasis Congress in San Francisco, CA, USA from October 25 to 27, 2019 (http://www.cancermetastasis.org). To be published in an upcoming Special Issue of Clinical and Experimental Metastasis: Novel Frontiers in Cancer Metastasis.

This review has been adapted from our chapter titled “Principle of Combination Immunotherapies” in Cancer Immunotherapy Principles and Practices, Second Edition, Society of Immunotherapy of Cancer [47].

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mehmi, I., Hamid, O. Immunotherapy of cancer in the era of checkpoint inhibitor. Clin Exp Metastasis 39, 231–237 (2022). https://doi.org/10.1007/s10585-021-10132-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10585-021-10132-9

Keywords

Search

Navigation