Immunotherapeutic intervention with oncolytic adenovirus in mouse mammary tumors
Heather Gibson1, Stephanie Munns1, Svend Freytag2
1Karmanos Cancer Institute; Wayne State University ; Detroit, MI USA.
Abstract:
The goal is to elucidate the immune modulating activity of an adenovirus (Adv) vector which showed therapeutic activity in human clinical trials. The oncolytic adenovirus (Adv/CD-TK) expressing two suicide genes was tested in two HER2/neu positive BALB/c mouse mammary tumor systems: rat neu-induced TUBO and human HER2-transfected D2F2/E2. Intra-tumoral (i.t.) Adv/CD-TK injection of TUBO tumor plus systemic prodrug therapy showed limited antitumor activity, not exceeding that by the virus itself. Antibody (Ab) to the virus was induced in Adv-/Luc-treated mice, to coincide with the loss of transgene expression. Low replication activity of adenoviruses in rodent cells may limit viral persistence. Host immunity against Adv or Adv-infected cells further mutes suicide gene activity. Treatment of TUBO tumors with Adv/CD-TK alone, however, induced neu-specific Ab responses. Treatment with Adv/CD-TK/GM (Adv/GM) that also expressed mouse granulocyte macrophage colony stimulating factor (GM-CSF), but without prodrug treatment, delayed tumor growth, enhanced anti-neu Ab production and conferred complete protection against secondary tumor challenge. D2F2/E2 tumor-bearing mice showed decreased tumor growth following i.t. Adv/GM treatment and they generated greater HER2-specific T-cell responses. These data suggest that i.t. injection of Adv itself induces immune reactivity to tumor-associated antigens and the encoded cytokine, GM-CSF, amplifies that immune response, resulting in tumor growth inhibition. Incorporation of suicide gene therapy did not improve the efficacy of Adv therapy in this mouse mammary tumor system. Oncolytic adenoviral therapy may be streamlined and improved by substituting the suicide genes with immune modulating genes to exploit tumor immunity for therapeutic benefit.
Insights
Oncolytic adenovirus therapy using suicide genes showed limited efficacy. However, an adenovirus expressing GM-CSF enhanced anti-tumor immunity and protection against HER2-positive mammary tumors.
Area of Science:
- Oncolytic virotherapy
- Cancer immunology
- Gene therapy
Background:
- Adenovirus (Adv) vectors are utilized for therapeutic purposes, showing promise in clinical trials.
- Oncolytic adenoviruses expressing suicide genes have been investigated for cancer treatment.
- Understanding the immune response to adenovirus vectors is crucial for optimizing their therapeutic potential.
Purpose of the Study:
- To investigate the immune-modulating activity of an oncolytic adenovirus vector (Adv/CD-TK) in HER2/neu-positive mouse mammary tumor models.
- To evaluate the therapeutic efficacy of Adv/CD-TK with and without prodrug therapy.
- To assess the impact of incorporating granulocyte macrophage colony-stimulating factor (GM-CSF) into the adenovirus vector (Adv/GM) on anti-tumor immunity and efficacy.
Main Methods:
- Testing Adv/CD-TK and Adv/GM in TUBO and D2F2/E2 mouse mammary tumor models.
- Administering intra-tumoral (i.t.) injections of adenovirus vectors.
- Evaluating antitumor activity, antibody (Ab) responses, transgene expression, and T-cell responses.
- Comparing efficacy with and without systemic prodrug therapy.
Main Results:
- Intra-tumoral Adv/CD-TK with prodrug therapy showed limited antitumor activity.
- Adenovirus (Adv) induced host immunity, potentially limiting transgene expression and efficacy.
- Adv/GM treatment alone delayed tumor growth, enhanced anti-neu antibody production, and provided protection against secondary tumor challenge.
- Adv/GM treatment in D2F2/E2 tumors reduced tumor growth and increased HER2-specific T-cell responses.
- Suicide gene therapy did not improve Adv efficacy in these models.
Conclusions:
- Intra-tumoral adenovirus injection can induce immune responses against tumor-associated antigens.
- GM-CSF expression by adenovirus vectors amplifies anti-tumor immune responses, leading to tumor growth inhibition.
- Replacing suicide genes with immune-modulating genes, like GM-CSF, may enhance oncolytic adenovirus therapy by leveraging tumor immunity.
