The expanding role for small molecules in immuno-oncology

Freeman, G. J. et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J. Exp. Med. 192, 1027–1034 (2000).

CAS  PubMed  PubMed Central  Article  Google Scholar 

Leach, D. R., Krummel, M. F. & Allison, J. P. Enhancement of antitumor immunity by CTLA-4 blockade. Science 271, 1734–1736 (1996).

CAS  PubMed  Article  Google Scholar 

Topalian, S. L., Drake, C. G. & Pardoll, D. M. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 27, 450–461 (2015).

CAS  PubMed  PubMed Central  Article  Google Scholar 

Goebeler, M. E. & Bargou, R. C. T cell-engaging therapies — BiTEs and beyond. Nat. Rev. Clin. Oncol. 17, 418–434 (2020).

PubMed  Article  Google Scholar 

Sanmamed, M. F. et al. Agonists of co-stimulation in cancer immunotherapy directed against CD137, OX40, GITR, CD27, CD28, and ICOS. Semin. Oncol. 42, 640–655 (2015).

CAS  PubMed  Article  Google Scholar 

Vonderheide, R. H. & Glennie, M. J. Agonistic CD40 antibodies and cancer therapy. Clin. Cancer Res. 19, 1035–1043 (2013).

CAS  PubMed  PubMed Central  Article  Google Scholar 

Haanen, J. B. A. G. et al. Management of toxicities from immunotherapy: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 28, iv119–iv142 (2017).

CAS  PubMed  Article  Google Scholar 

Ramos-Casals, M. et al. Immune-related adverse events of checkpoint inhibitors. Nat. Rev. Dis. Prim. 6, 38 (2020).

PubMed  Article  Google Scholar 

Hanahan, D. Hallmarks of cancer: new dimensions. Cancer Discov. 12, 31–46 (2022).

CAS  PubMed  Article  Google Scholar 

Galluzzi, L. et al. Consensus guidelines for the definition, detection and interpretation of immunogenic cell death. J. Immunother. Cancer 8, e000337 (2020).

PubMed  PubMed Central  Article  Google Scholar 

Robert, C. et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N. Engl. J. Med. 364, 2517–2526 (2011).

CAS  PubMed  Article  Google Scholar 

Ménétrier-Caux, C., Ray-Coquard, I., Blay, J.-Y. & Caux, C. Lymphopenia in cancer patients and its effects on response to immunotherapy: an opportunity for combination with cytokines? J. Immunother. Cancer 7, 85 (2019).

PubMed  PubMed Central  Article  Google Scholar 

Lito, P., Rosen, N. & Solit, D. B. Tumor adaptation and resistance to RAF inhibitors. Nat. Med. 19, 1401–1409 (2013).

CAS  PubMed  Article  Google Scholar 

Caunt, C. J., Sale, M. J., Smith, P. D. & Cook, S. J. MEK1 and MEK2 inhibitors and cancer therapy: the long and winding road. Nat. Rev. Cancer 15, 577–592 (2015).

CAS  PubMed  Article  Google Scholar 

Ribas, A. et al. Extended 5-year follow-up results of a phase Ib study (BRIM7) of vemurafenib and cobimetinib in BRAF-mutant melanoma. Clin. Cancer Res. 26, 46 (2020).

CAS  PubMed  Article  Google Scholar 

Robert, C. et al. Five-year outcomes with dabrafenib plus trametinib in metastatic melanoma. N. Engl. J. Med. 381, 626–636 (2019).

CAS  PubMed  Article  Google Scholar 

Garbe, C. et al. European consensus-based interdisciplinary guideline for melanoma. Part 2: treatment–update 2019. Eur. J. Cancer 126, 159–177 (2020).

CAS  PubMed  Article  Google Scholar 

Ribas, A. et al. Combined BRAF and MEK inhibition with PD-1 blockade immunotherapy in BRAF-mutant melanoma. Nat. Med. 25, 936–940 (2019).

CAS  PubMed  PubMed Central  Article  Google Scholar 

Sullivan, R. J. et al. Atezolizumab plus cobimetinib and vemurafenib in BRAF-mutated melanoma patients. Nat. Med. 25, 929–935 (2019).

CAS  PubMed  Article  Google Scholar 

Hu-Lieskovan, S. et al. Improved antitumor activity of immunotherapy with BRAF and MEK inhibitors in BRAFV600E melanoma. Sci. Transl. Med. 7, 279ra241 (2015). First preclinical evidence of the pro-immunogenic impact of MEK inhibitors.

Article  CAS  Google Scholar 

Ebert, P. J. R. et al. MAP kinase inhibition promotes T cell and anti-tumor activity in combination with PD-L1 checkpoint blockade. Immunity 44, 609–621 (2016).

CAS  PubMed  Article  Google Scholar 

Dushyanthen, S. et al. Agonist immunotherapy restores T cell function following MEK inhibition improving efficacy in breast cancer. Nat. Commun. 8, 606 (2017).

PubMed  PubMed Central  Article  CAS  Google Scholar 

Baumann, D. et al. Proimmunogenic impact of MEK inhibition synergizes with agonist anti-CD40 immunostimulatory antibodies in tumor therapy. Nat. Commun. 11, 2176 (2020).

CAS  PubMed  PubMed Central  Article  Google Scholar 

Baumann, D. et al. p38 MAPK signaling in M1 macrophages results in selective elimination of M2 macrophages by MEK inhibition. J. Immunother. Cancer 9, e002319 (2021).

PubMed  PubMed Central  Article  Google Scholar 

Dörrie, J. et al. BRAF and MEK inhibitors influence the function of reprogrammed T cells: consequences for adoptive T-cell therapy. Int. J. Mol. Sci. 19, 289 (2018).

PubMed Central  Article  CAS  Google Scholar 

Ferrucci, P. F. et al. KEYNOTE-022 part 3: a randomized, double-blind, phase 2 study of pembrolizumab, dabrafenib, and trametinib in BRAF-mutant melanoma. J. Immunother. Cancer 8, e001806 (2020).

PubMed  PubMed Central  Article  Google Scholar 

Gutzmer, R. et al. Atezolizumab, vemurafenib, and cobimetinib as first-line treatment for unresectable advanced BRAFV600 mutation-positive melanoma (IMspire150): primary analysis of the randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 395, 1835–1844 (2020). Clinical trial that fulfilled the concept of synergy between MEK/BRAF inhibition and ICI, resulting in FDA approval of this triple regimen for BRAF-mutated melanoma.

CAS  PubMed  Article  Google Scholar 

Dummer, R. et al. Combined PD-1, BRAF and MEK inhibition in advanced BRAF-mutant melanoma: safety run-in and biomarker cohorts of COMBI-i. Nat. Med. 26, 1557–1563 (2020).

CAS  PubMed  Article  Google Scholar 

Dummer, R. et al. Randomized phase III trial evaluating spartalizumab plus dabrafenib and trametinib for BRAF V600-mutant unresectable or metastatic melanoma. J. Clin. Oncol. 40, 1428–1438 (2022).

CAS  PubMed  PubMed Central  Article  Google Scholar 

Canon, J. et al. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature 575, 217–223 (2019). First preclinical evidence for synergy of a mutant-KRAS-specific drug with ICI.

CAS  PubMed  Article  Google Scholar 

Briere, D. M. et al. The KRAS(G12C) inhibitor MRTX849 reconditions the tumor immune microenvironment and sensitizes tumors to checkpoint inhibitor therapy. Mol. Cancer Ther. 20, 975–985 (2021).

CAS  PubMed  PubMed Central  Article  Google Scholar 

Łuksza, M. et al. A neoantigen fitness model predicts tumour response to checkpoint blockade immunotherapy. Nature 551, 517–520 (2017).

PubMed  PubMed Central  Article  CAS  Google Scholar 

Eng, C. et al. Atezolizumab with or without cobimetinib versus regorafenib in previously treated metastatic colorectal cancer (IMblaze370): a multicentre, open-label, phase 3, randomised, controlled trial. Lancet Oncol. 20, 849–861 (2019).

CAS  PubMed  Article  Google Scholar 

Haigis, K. M. KRAS alleles: the devil is in the detail. Trends Cancer 3, 686–697 (2017).

CAS  PubMed  PubMed Central  Article  Google Scholar 

Hack, S. P., Zhu, A. X. & Wang, Y. Augmenting anticancer immunity through combined targeting of angiogenic and PD-1/PD-L1 pathways: challenges and opportunities. Front. Immunol. 11, 598877 (2020).

CAS  PubMed  PubMed Central  Article  Google Scholar 

Socinski, M. A. et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N. Engl. J. Med. 378, 2288–2301 (2018). The clinical study presented in this paper is the first to show clinical benefit of combining a drug that inhibits the VEGF/VEGFR pathway with ICI. Although this study provided proof of concept for the VEGF-blocking Ab bevacizumab, the two publications below demonstrate that this synergy could also be achieved by using small-molecule VEGFR inhibitor axitinib.

CAS  PubMed  Article  Google Scholar 

Motzer, R. J. et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N. Engl. J. Med. 380, 1103–1115 (2019).

CAS  PubMed  PubMed Central  Article  Google Scholar 

Rini, B. I. et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N. Engl. J. Med. 380, 1116–1127 (2019).

CAS  PubMed  Article  Google Scholar 

留言 (0)

沒有登入
gif