Aiken et al. demonstrated that neoadjuvant vaccination with an intratumorally delivered anti-GD2-targeted IL-2 (IT-IC; an immunocytokine) did not inhibit primary tumor growth, but led to increased CD8+ T cell infiltration, a higher CD8:Treg ratio, and development of immunologic memory against contralateral flank rechallenge post-resection in a B78 melanoma model. Immunological memory development was independent of challenge timing after surgery. Neoadjuvant IT-IC in GD2+ B16 melanoma led to less toxic wound healing (compared to radiation therapy plus IT-IC), and reduced lung metastasis in a CD4+ T cell-dependent manner after rechallenge with GD2- B16 cells.
Contributed by Shishir Pant
BACKGROUND: Surgical resection remains an important component of multimodality treatment for most solid tumors. Neoadjuvant immunotherapy has several potential advantages, including in-situ tumor vaccination and pathologic assessment of response in the surgical specimen. We previously described an in-situ tumor vaccination strategy in melanoma using local radiation (RT) and an intratumoral injection of tumor-specific anti-GD2 immunocytokine (IT-IC). Here we tested whether neoadjuvant in-situ tumor vaccination using anti-GD2 immunocytokine and surgical resection, without RT, could generate immunologic memory capable of preventing recurrence or distant metastasis. METHODS: Mice bearing GD2 expressing B78 melanoma tumors were treated with neoadjuvant radiation, IT-IC, or combined RT + IT-IC. Surgical resection was performed following neoadjuvant immunotherapy. Immune infiltrate was assessed in the resection specimens. Mice were rechallenged with either B78 contralateral flank tumors or pulmonary seeding of non-GD2 expressing B16 melanoma metastasis induced experimentally. Rejection of rechallenge in mice treated with the various treatment regimens was considered evidence of immunologic memory. RESULTS: Neoadjuvant IT-IC and surgical resection resulted in increased CD8 T cell infiltration, a higher CD8:regulatory T cell ratio, and immunologic memory against contralateral flank rechallenge. The timing of resection did not significantly impact the development of memory, which was present as early as the day of surgery. There was less local wound toxicity with neoadjuvant IT-IC compared with neoadjuvant RT +IT IC. Neoadjuvant IT-IC and resection resulted in the rejection of B16 lung metastasis in a CD4 T cell dependent manner. CONCLUSIONS: Neoadjuvant IT-IC generates immunologic memory capable of preventing distant metastasis despite limited efficacy against large primary melanoma tumors. By combining neoadjuvant tumor vaccination and surgery, the toxicity of local RT was avoided. These preclinical data support further investigation regarding the use of neoadjuvant IT-IC in patients with melanoma at high risk for occult distant disease.
Author Info: (1) Department of Surgery, University of Wisconsin, Madison, Wisconsin, USA. (2) Department of Human Oncology, University of Wisconsin, Madison, Wisconsin, USA. (3) Department of H
Author Info: (1) Department of Surgery, University of Wisconsin, Madison, Wisconsin, USA. (2) Department of Human Oncology, University of Wisconsin, Madison, Wisconsin, USA. (3) Department of Human Oncology, University of Wisconsin, Madison, Wisconsin, USA. (4) Department of Human Oncology, University of Wisconsin, Madison, Wisconsin, USA. (5) Department of Human Oncology, University of Wisconsin, Madison, Wisconsin, USA. (6) Department of Human Oncology, University of Wisconsin, Madison, Wisconsin, USA. Arrowhead Pharmaceuticals Inc, Madison, Wisconsin, USA. (7) Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, Wisconsin, USA. (8) Provenance Biopharmaceuticals, Carlisle, Massachusetts, USA. (9) Department of Human Oncology, University of Wisconsin, Madison, Wisconsin, USA. (10) Department of Human Oncology, University of Wisconsin, Madison, Wisconsin, USA. (11) Department of Human Oncology, University of Wisconsin, Madison, Wisconsin, USA pmsondel@humonc.wisc.edu. Department of Pediatrics, University of Wisconsin, Madison, Wisconsin, USA.
