The efficacy of tumor debulking surgery is improved by adjuvant immunotherapy using imiquimod and anti-CD40

BMC Cancer

Andrea Khong³  Amanda L Cleaver³  Muhammad Fahmi Alatas³  Ben C Wylie¹  Theresa Connor¹  Scott A Fisher³  Steve Broomfield²  Willem J Lesterhuis³  Andrew J Currie²  Richard A Lake³  Bruce W Robinson³ 

[1] Current address: Telethon Kids Institute, Perth, Western Australia

[2] School of Veterinary and Life Sciences, Murdoch University, Perth, Western Australia

[3] National Centre for Asbestos Related Diseases, Perth, Western Australia

关键词: Mesothelioma;    Anti-CD40;    Imiquimod;    Immunotherapy;    Debulk;    Tumor;    Surgery;   

Others  :  1117860
DOI  :  10.1186/1471-2407-14-969

 received in 2014-09-10, accepted in 2014-12-11,  发布年份 2014

【 摘 要 】

Background

Tumor debulking surgery followed by adjuvant chemotherapy or radiotherapy is a standard treatment for many solid malignancies. Although this approach can be effective, it often has limited success against recurrent or metastatic cancers and new multimodality approaches are needed. Adjuvant immunotherapy is another potentially effective approach. We therefore tested the efficacy of the TLR7 agonist imiquimod (IMQ) combined with agonistic anti-CD40 in an incomplete debulking model of malignant mesothelioma.

Methods

Established subcutaneous murine ABA-HA mesothelioma tumors in BALB/c mice were surgically debulked by 75% and treated with either: i) saline; ii) intratumoral IMQ; iii) systemic anti-CD40 antibody, or using a combination of IMQ and anti-CD40. Tumour growth and survival were monitored, and the role of anti-tumor CD4 and CD8 T cells in therapeutic responses was determined.

Results

The combination therapy of partial debulking surgery, IMQ and anti-CD40 significantly delayed tumor growth in a CD8 T cell dependent manner, and promoted tumor regression in 25% of animals with establishment of immunological memory. This response was associated with an increase in ICOS+ CD8 T cells and tumor-specific CTL activity in tumor draining lymph nodes along with an increase in ICOS+ CD8 T cells in responding tumours.

Conclusions

We show that the post-surgical environment can be significantly altered by the co-administration of adjuvant IMQ and anti-CD40, resulting in strong, systemic anti-tumor activity. Both adjuvants are available for clinical use/trial, hence this treatment regimen has clear translational potential.

【 授权许可】

   
2014 Khong et al.; licensee BioMed Central.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

Figure 7.

Figure 8.

【 参考文献 】

• [1]Carrato A: Adjuvant treatment of colorectal cancer. Gastrointest Cancer Res 2008, 2(4 Suppl):S42-S46.
• [2]Cole BF, Gelber RD, Gelber S, Coates AS, Goldhirsch A: Polychemotherapy for early breast cancer: an overview of the randomised clinical trials with quality-adjusted survival analysis. Lancet 2001, 358(9278):277-286.
• [3]Yan TD, Cao CQ, Boyer M, Tin MM, Kennedy C, McLean J, Bannon PG, McCaughan BC: Improving survival results after surgical management of malignant pleural mesothelioma: an Australian institution experience. Ann Thorac Cardiovasc Surg 2011, 17(3):243-249.
• [4]Nowak AK: Immunological checkpoint inhibitors enter adolescence. Lancet Oncol 2013, 14(11):1035-1037.
• [5]Vacchelli E, Galluzzi L, Eggermont A, Fridman WH, Galon J, Sautes-Fridman C, Tartour E, Zitvogel L, Kroemer G: Trial watch: FDA-approved Toll-like receptor agonists for cancer therapy. Oncoimmunology 2012, 1(6):894-907.
• [6]Kurts C, Robinson BW, Knolle PA: Cross-priming in health and disease. Nat Rev Immunol 2010, 10(6):403-414.
• [7]Beatty GL, Chiorean EG, Fishman MP, Saboury B, Teitelbaum UR, Sun W, Huhn RD, Song W, Li D, Sharp LL, Torigian DA, O'Dwyer PJ, Vonderheide RH: CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science 2011, 331(6024):1612-1616.
• [8]Vonderheide RH, Burg JM, Mick R, Trosko JA, Li D, Shaik MN, Tolcher AW, Hamid O: Phase I study of the CD40 agonist antibody CP-870,893 combined with carboplatin and paclitaxel in patients with advanced solid tumors. Oncoimmunology 2013, 2(1):e23033.
• [9]Stumbles PA, Himbeck R, Frelinger JA, Collins EJ, Lake RA, Robinson BW: Cutting edge: tumor-specific CTL are constitutively cross-armed in draining lymph nodes and transiently disseminate to mediate tumor regression following systemic CD40 activation. J Immunol 2004, 173(10):5923-5928.
• [10]Broomfield SA, van der Most RG, Prosser AC, Mahendran S, Tovey MG, Smyth MJ, Robinson BW, Currie AJ: Locally administered TLR7 agonists drive systemic antitumor immune responses that are enhanced by anti-CD40 immunotherapy. J Immunol 2009, 182(9):5217-5224.
• [11]Marzo AL, Lake RA, Robinson BW, Scott B: T-cell receptor transgenic analysis of tumor-specific CD8 and CD4 responses in the eradication of solid tumors. Cancer Res 1999, 59(5):1071-1079.
• [12]Oehen S, Brduscha-Riem K: Differentiation of naive CTL to effector and memory CTL: correlation of effector function with phenotype and cell division. J Immunol 1998, 161(10):5338-5346.
• [13]Lyons AB, Parish CR: Determination of lymphocyte division by flow cytometry. J Immunol Methods 1994, 171(1):131-137.
• [14]Currie AJ, van der Most RG, Broomfield SA, Prosser AC, Tovey MG, Robinson BW: Targeting the effector site with IFN-alphabeta-inducing TLR ligands reactivates tumor-resident CD8 T cell responses to eradicate established solid tumors. J Immunol 2008, 180(3):1535-1544.
• [15]Sinha P, Clements VK, Ostrand-Rosenberg S: Reduction of myeloid-derived suppressor cells and induction of M1 macrophages facilitate the rejection of established metastatic disease. J Immunol 2005, 174(2):636-645.
• [16]Kruklitis RJ, Singhal S, Delong P, Kapoor V, Sterman DH, Kaiser LR, Albelda SM: Immuno-gene therapy with interferon-beta before surgical debulking delays recurrence and improves survival in a murine model of malignant mesothelioma. J Thorac Cardiovasc Surg 2004, 127(1):123-130.
• [17]Predina J, Eruslanov E, Judy B, Kapoor V, Cheng G, Wang LC, Sun J, Moon EK, Fridlender ZG, Albelda S, Singhal S: Changes in the local tumor microenvironment in recurrent cancers may explain the failure of vaccines after surgery. Proc Natl Acad Sci U S A 2013, 110(5):E415-E424.
• [18]Marabelle A, Kohrt H, Sagiv-Barfi I, Ajami B, Axtell RC, Zhou G, Rajapaksa R, Green MR, Torchia J, Brody J, Luong R, Rosenblum MD, Steinman L, Levitsky HI, Tse V, Levy R: Depleting tumor-specific Tregs at a single site eradicates disseminated tumors. J Clin Invest 2013, 123(6):2447-2463.
• [19]Nelson DJ: Turning the tumor microenvironment into a self vaccine site. Oncoimmunology 2012, 1(6):989-991.
• [20]Jackaman C, Nelson DJ: Intratumoral interleukin-2/agonist CD40 antibody drives CD4+ − independent resolution of treated-tumors and CD4+ − dependent systemic and memory responses. Cancer Immunol Immunother 2012, 61(4):549-560.
• [21]Jackaman C, Lew AM, Zhan Y, Allan JE, Koloska B, Graham PT, Robinson BW, Nelson DJ: Deliberately provoking local inflammation drives tumors to become their own protective vaccine site. Int Immunol 2008, 20(11):1467-1479.
• [22]Broomfield S, Currie A, van der Most RG, Brown M, van Bruggen I, Robinson BW, Lake RA: Partial, but not complete, tumor-debulking surgery promotes protective antitumor memory when combined with chemotherapy and adjuvant immunotherapy. Cancer Res 2005, 65(17):7580-7584.
• [23]Khong A, Brown MD, Vivian JB, Robinson BW, Currie AJ: Agonistic anti-CD40 antibody therapy is effective against postoperative cancer recurrence and metastasis in a murine tumor model. J Immunother 2013, 36(7):365-372.
• [24]Warger T, Rechtsteiner G, Schmid B, Osterloh P, Schild H, Radsak MP: Transcutaneous immunization with imiquimod is amplified by CD40 ligation and results in sustained cytotoxic T-lymphocyte activation and tumor protection. Clin Rev Allergy Immunol 2007, 32(1):57-66.
• [25]Aranda F, Llopiz D, Diaz-Valdes N, Riezu-Boj JI, Bezunartea J, Ruiz M, Martinez M, Durantez M, Mansilla C, Prieto J, Lasarte JJ, Borrás-Cuesta F, Sarobe P: Adjuvant combination and antigen targeting as a strategy to induce polyfunctional and high-avidity T-cell responses against poorly immunogenic tumors. Cancer Res 2011, 71(9):3214-3224.
• [26]Khong A, Nelson DJ, Nowak AK, Lake RA, Robinson BW: The use of agonistic anti-CD40 therapy in treatments for cancer. Int Rev Immunol 2012, 31(4):246-266.
• [27]Murphy WJ, Welniak L, Back T, Hixon J, Subleski J, Seki N, Wigginton JM, Wilson SE, Blazar BR, Malyguine AM, Sayers TJ, Wiltrout RH: Synergistic anti-tumor responses after administration of agonistic antibodies to CD40 and IL-2: coordination of dendritic and CD8+ cell responses. J Immunol 2003, 170(5):2727-2733.
• [28]Lesterhuis WJ, Salmons J, Nowak AK, Rozali EN, Khong A, Dick IM, Harken JA, Robinson BW, Lake RA: Synergistic effect of CTLA-4 blockade and cancer chemotherapy in the induction of anti-tumor immunity. PLoS One 2013, 8(4):e61895.
• [29]Rozali EN, Hato SV, Robinson BW, Lake RA, Lesterhuis WJ: Programmed death ligand 2 in cancer-induced immune suppression. Clin Dev Immunol 2012, 2012:656340.