Immunotherapy Achievements, Awards, & Prizes
Immunotherapy Achievements, Awards, & Prizes - Research at Peter Mac
|Awards & Prizes|
|Assoc. Prof. Phil Darcy|
|Assoc. Prof. Michael Kershaw|
|Dr Hollie Pegram|
|Recent Invited Presentations|
|Assoc. Prof. Phil Darcy|
|Assoc. Professor Michael Kershaw|
|Recent Research Achievements|
|THREE AGONIST ANTIBODIES IN COMBINATION WITH HIGH-DOSE IL-2 ERADICATE ORTHOTOPIC KIDNEY CANCER IN MICE.|
Combination immunotherapies can be effective against subcutaneous tumors in mice but the effect against orthotopic malignant disease is less well characterized. In particular, a combination of three agonist antibodies, termed Tri-mAb, consisting of anti-DR5, anti-CD40 and anti-CD137 has previously been demonstrated to eradicate a large proportion of subcutaneous renal cell carcinoma (Renca) tumors (75% long-term survival), but the effect against orthotopic disease is not known. To determine the relative response of orthotopic tumors, we inoculated Renca into the kidney followed by treatment with Tri-mAb. We found that orthotopic tumors responded much less to treatment (~13% survival), but a significant improvement in survival was achieved through the addition of IL-2 to the treatment regimen (55% survival). All three agonist antibodies and high dose IL-2, 100,000 IU for up to six doses, were required. CD8+ T cells were also required for optimal anti-tumor responses. Coadministration of IL-2 led to enhanced T cell activity as demonstrated by an increased frequency of IFN-gamma-producing T cells in tumor-draining lymph nodes, which may have contributed to the observed improvement of therapy against kidney tumors. Responses of subcutaneous tumors to immunotherapy do not necessarily reflect how orthotopic tumors respond. The use of combination immunotherapy stimulating multiple facets of immunity and including cytokine support for T cells can induce effective anti-tumor responses against orthotopic and metastatic tumors.
ADOPTIVE TRANSFER OF GENE-MODIFIED T CELLS CAN MEDIATE REJECTION OF ESTABLISHED TUMOUR IN THE ABSENCE OF AUTOIMMUNITY
Adoptive immunotherapy involving genetic modification of T cells with antigen-specific chimeric single-chain receptors is a promising approach for treatment of cancer. To determine whether gene-modified T cells could induce anti-tumour effects without associated autoimmune pathology we assessed the ability of T cells expressing an anti-Her-2 chimeric receptor to eradicate tumour in Her-2 transgenic mice that express human Her-2 as a self-antigen in brain and mammary tissue. In adoptive transfer studies, we demonstrated significant improvement in the survival of mice bearing Her-2+ 24JK tumour following administration of anti-Her-2 T cells compared to control T cells. The incorporation of a lymphodepleting step prior to adoptive transfer of anti-Her-2 T cells and administration of IL-2 was found to further enhance survival of recipient mice and impact significantly on established disease which correlated with localization of transferred T cells at the tumour site. Furthermore an antigen-specific recall response could be induced in long term surviving mice following rechallenge with Her-2+ tumour. Importantly, anti-tumour effects were not associated with any autoimmune pathology to normal tissue expressing Her-2 antigen following therapy. This study highlights the therapeutic potential of using gene-engineered T cells as a safe and effective treatment for cancer.
TOLL-LIKE RECEPTOR TRIGGERING AND T CELL COSTIMULATION INDUCE POTENT ANTI-TUMOR IMMUNITY IN MICE.
To simultaneously direct multiple immune components against cancer we combined the Toll-like receptor agonist CpG 1826 with a T cell costimulatory antibody specific for CD137. This combination was demonstrated to eradicate established malignancies in mice. Crucial roles for CD8+ T cells, NK cells and interferons were demonstrated. CpG and anti-CD137 injection led to activation of dendritic cells and optimal expansion of activated T cells in the blood. Gene expression analysis revealed that CpG upregulated a variety of genes, with those associated with macrophage biology being particularly well represented, but subsequent studies demonstrated that depletion of macrophages in vivo led to an enhancement of therapy, which has not been previously reported. Long-term surviving mice were resistant to tumor rechallenge, demonstrating immunological memory. In addition, we demonstrate, for the first time, that mice lacking B cells have a total loss of a recall response against tumor, suggesting a role for B cells in the induction of anti-tumor immunological memory. This study provides support for the use of combination treatments stimulating multiple facets of immunity for the effective immunotherapy of cancer.
COMBINING ADOPTIVE IMMUNOTHERAPY WITH TOLL-LIKE RECEPTOR (TLR) AGONISTS FOR THE TREATMENT OF MELANOMA IN MICE.
Adoptive immunotherapy is showing great promise for the treatment of melanoma although current treatment regimens are associated with significant side effects, and tumour regressions are not always long lasting. In attempts to enhance adoptive immunotherapy, we have combined T cell transfer with intratumoural injection of TLR agonists that mimic infection. We have shown that approximately 20% of mice can achieve long-term regression of established melanoma using this therapy. In addition, we have demonstrated that interferon produced by the transferred T cells plays a crucial role in the anti-tumour effects.
ADOPTIVE TRANSFER OF GENE-MODIFIED PRIMARY NK CELLS CAN SPECIFICALLY INHIBIT TUMOUR PROGRESSION IN VIVO.
Natural Killer (NK) cells hold great potential for improving the immunotherapy of cancer. Nevertheless, tumor cells can effectively escape NK cell mediated apoptosis through interaction of MHC molecules with NK cell inhibitory receptors. Thus, to harness NK cell effector function against tumors, we employed Amaxa gene transfer technology to gene-modify primary mouse NK cells with a chimeric single chain (scFv) receptor specific for the human erbB2 tumor-associated antigen. The chimeric receptor was composed of the extracellular scFv anti-erbB2 antibody linked to the transmembrane and cytoplasmic CD28 and TCR-ζ signaling domains (scFv-CD28-ζ). In this study we demonstrated that mouse NK cells gene-modified with this chimera could specifically mediate enhanced killing of an erbB2+ MHC class I+ lymphoma in a perforin-dependent manner. Expression of the chimera did not interfere with NK cell-mediated cytotoxicity mediated by endogenous NK receptors. Furthermore, adoptive transfer of gene-modified NK cells significantly enhanced the survival of RAG mice bearing established intraperitoneal RMA-erbB2+ lymphoma. In summary, this data suggests that utilization of genetically modified NK cells could broaden the scope of cancer immunotherapy for patients.
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|Associate Professor Phil Darcy (left)|
Associate Professor Michael Kershaw (right)
|Dr Linda Howland|
Dr Christel Devaud
Dr Liza John