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Tumor Regression and Cure Depends on Sustained Th1 Responses

Dai, Min ; Hellstrom, Ingegerd ; Yip, Yuen Y. ; Sjögren, Hans Olov LU and Hellstrom, Karl Erik (2018) In Journal of Immunotherapy 41(8). p.369-378
Abstract

While immunomodulatory monoclonal antibodies (mAbs) have therapeutic efficacy against many tumors, few patients are cured. Attempting to improve their therapeutic efficacy we have applied the TC1 mouse lung carcinoma model and injected established subcutaneous tumors intratumorally with 3 weekly doses of various combinations of mAbs. Combinations of mAbs to CTLA4/PD1/CD137 (the 3 mAb combination) and to CTLA4/PD1/CD137/CD19 (the 4 mAb combination) were most efficacious to induce complete regression of both the injected tumor and an untreated tumor in the same mouse. Tumor cure was consistently associated with shifting a Th2 to a Th1 response in tumor-draining lymph nodes and spleen and it involved epitope specific and long-lived memory... (More)

While immunomodulatory monoclonal antibodies (mAbs) have therapeutic efficacy against many tumors, few patients are cured. Attempting to improve their therapeutic efficacy we have applied the TC1 mouse lung carcinoma model and injected established subcutaneous tumors intratumorally with 3 weekly doses of various combinations of mAbs. Combinations of mAbs to CTLA4/PD1/CD137 (the 3 mAb combination) and to CTLA4/PD1/CD137/CD19 (the 4 mAb combination) were most efficacious to induce complete regression of both the injected tumor and an untreated tumor in the same mouse. Tumor cure was consistently associated with shifting a Th2 to a Th1 response in tumor-draining lymph nodes and spleen and it involved epitope specific and long-lived memory T cells as well as M1 macrophages. This shift and accompanying tumor rejection was harder to achieve as the treated tumors increased in size. Relapse of tumors which had initially regressed following treatment with immunomodulatory mAbs was associated with return of a Th2 microenvironment in tumors, tumor-draining lymph nodes and spleens rather than the emergence of immune-resistant tumor cells. While mAbs to CTLA4 plus PD-1 were therapeutically ineffective, combining the 2 of them with intraperitoneal cisplatin, 10 mg/kg, induced long-term complete tumor regression in most mice with small TC1 tumors and the therapeutic efficacy against larger tumors improved by administrating cisplatin together with the 3 or 4 mAb combination.

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author
; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
cisplatin, immunomodulatory antibodies, immunotherapy, tumor microenvironment
in
Journal of Immunotherapy
volume
41
issue
8
pages
369 - 378
publisher
Lippincott Williams & Wilkins
external identifiers
  • pmid:29912725
  • scopus:85048634535
ISSN
1524-9557
DOI
10.1097/CJI.0000000000000231
language
English
LU publication?
yes
id
0f4b4d4b-ae07-426d-ae9b-ac540884b823
date added to LUP
2018-06-28 14:04:02
date last changed
2024-06-10 14:27:39
@article{0f4b4d4b-ae07-426d-ae9b-ac540884b823,
  abstract     = {{<p>While immunomodulatory monoclonal antibodies (mAbs) have therapeutic efficacy against many tumors, few patients are cured. Attempting to improve their therapeutic efficacy we have applied the TC1 mouse lung carcinoma model and injected established subcutaneous tumors intratumorally with 3 weekly doses of various combinations of mAbs. Combinations of mAbs to CTLA4/PD1/CD137 (the 3 mAb combination) and to CTLA4/PD1/CD137/CD19 (the 4 mAb combination) were most efficacious to induce complete regression of both the injected tumor and an untreated tumor in the same mouse. Tumor cure was consistently associated with shifting a Th2 to a Th1 response in tumor-draining lymph nodes and spleen and it involved epitope specific and long-lived memory T cells as well as M1 macrophages. This shift and accompanying tumor rejection was harder to achieve as the treated tumors increased in size. Relapse of tumors which had initially regressed following treatment with immunomodulatory mAbs was associated with return of a Th2 microenvironment in tumors, tumor-draining lymph nodes and spleens rather than the emergence of immune-resistant tumor cells. While mAbs to CTLA4 plus PD-1 were therapeutically ineffective, combining the 2 of them with intraperitoneal cisplatin, 10 mg/kg, induced long-term complete tumor regression in most mice with small TC1 tumors and the therapeutic efficacy against larger tumors improved by administrating cisplatin together with the 3 or 4 mAb combination.</p>}},
  author       = {{Dai, Min and Hellstrom, Ingegerd and Yip, Yuen Y. and Sjögren, Hans Olov and Hellstrom, Karl Erik}},
  issn         = {{1524-9557}},
  keywords     = {{cisplatin; immunomodulatory antibodies; immunotherapy; tumor microenvironment}},
  language     = {{eng}},
  month        = {{06}},
  number       = {{8}},
  pages        = {{369--378}},
  publisher    = {{Lippincott Williams & Wilkins}},
  series       = {{Journal of Immunotherapy}},
  title        = {{Tumor Regression and Cure Depends on Sustained Th1 Responses}},
  url          = {{http://dx.doi.org/10.1097/CJI.0000000000000231}},
  doi          = {{10.1097/CJI.0000000000000231}},
  volume       = {{41}},
  year         = {{2018}},
}