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

Our plain-English summary of The efficacy of tumor debulking surgery is improved by adjuvant immunotherapy using imiquimod and anti-CD40, by A. Khong, A.L. Cleaver, M. Fahmi Alatas, et al (BMC Cancer, 2014).

The study

• Authors: A. Khong, A.L. Cleaver, M. Fahmi Alatas, B.C. Wylie, T. Connor, S.A. Fisher, S. Broomfield, W.J. Lesterhuis, A.J. Currie, R.A. Lake, B.W. Robinson
• Journal: BMC Cancer
• Published: 2014;14:969
• Cited by: 24 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

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.

In plain English

This was a laboratory experiment in mice. It did not study people or asbestos exposure. The authors grew AB1-HA mouse mesothelioma tumors under the skin of female BALB/c mice and first compared surgically removing different amounts of tumor. Complete removal succeeded in 4 out of 6 mice, which then stayed tumor-free for more than 100 days. Removing 50% or less gave results indistinguishable from sham-treated mice. The main treatment experiments used removal of about 75% of the tumor. Mice then received imiquimod (IMQ) injected into the remaining tumor, an anti-CD40 antibody, both, or no added treatment. After 75% removal, adding IMQ delayed tumor growth by up to 30 days, and 20% of mice survived beyond 50 days. This benefit depended on CD8 T cells. Adding both IMQ and anti-CD40 gave a survival advantage of 10 days over surgery alone (p less than 0.0001). In this group, tumor-specific killer T cell activity in the lymph nodes draining the tumor rose to over 45%. The authors concluded that the period after surgery should be considered an opportunity to give immune-stimulating drugs, an approach they said warrants future clinical study.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Animal experiment: partial surgical removal of implanted mouse mesothelioma tumors, followed by immunotherapy
• Who was studied: Female BALB/c mice, 6 to 8 weeks old, from the Animal Resources Centre (Western Australia), kept at the University of Western Australia
• Exposure: No asbestos or fiber exposure was studied. Mice were given AB1-HA mouse mesothelioma tumor cells under the skin. In the main experiments, about 75% of the tumor was removed, and mice were then treated with IMQ (50 μg injected into the tumor once daily for 6 days, starting at surgery) and/or anti-CD40 antibody (100 μg injected into the abdomen).
• Main results:
  • In the mice where complete removal of the tumor was attempted, it succeeded in 4 out of 6, and those mice survived tumor-free for more than 100 days
  • When 50% or less of the tumor was removed, tumor growth and tumor-free survival were indistinguishable from sham-treated mice
  • After 75% removal, fewer than 20% of animals survived tumor-free
  • In mice given surgery alone, tumor-specific killer T cell (CTL) responses were below the limits of detection
  • In mice given 75% removal plus IMQ, tumor growth was delayed by up to 30 days and 20% survived more than 50 days. Surviving mice resisted a second injection of tumor cells, which the authors took as a sign of tumor-specific immune memory.
  • In mice given 75% removal plus IMQ, removing CD8 T cells significantly decreased survival (p = 0.0004 compared with 75% removal plus IMQ)
  • Mice given 75% removal plus IMQ plus anti-CD40 had a survival advantage of 10 days over mice given surgery alone
  • With surgery plus anti-CD40, CTL activity was 19% in the draining lymph nodes, 6% in the non-draining lymph nodes and 4% in the spleen. With surgery alone, the figures were 3%, 3% and 1%.
  • With surgery plus IMQ plus anti-CD40, CTL killing rose to over 45% in the draining lymph nodes (p less than 0.001), 15% in the non-draining lymph nodes (p less than 0.05) and 15% in the spleen (p less than 0.01)
  • In mice given anti-CD40 (with surgery alone or with surgery plus IMQ), the percentages of CD4 and CD8 T cells in the draining lymph nodes fell significantly. The authors reported that the activation of these cells rose, particularly CD8 T cells.
• The authors' conclusion: The authors concluded that the period after surgery should be considered an opportunity to give immune-modulating drugs against inoperable, residual or metastatic tumor, an approach they said warrants future clinical study
• Limitations the authors state:
  • The authors did not include control injections of saline into the tumor, relying instead on their previous studies
  • The authors stated that further work is needed to identify which therapies help which cancers, and by what mechanisms

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Cytoreductive Surgery, Immunotherapy, Chemotherapy, Mesothelioma.

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