A novel immunization strategy using cytokine/chemokines induces new effective systemic immune responses, and frequent complete regressions of human metastatic melanoma

ABSTRACT

Immune responses have been elicited by a variety of cancer vaccines, but seldom induce regressions of established cancers in humans. As a novel therapeutic immunization strategy, we tested the hypothesis that multiple cytokines/chemokines secreted early in secondary responses ex-vivo might mimic the secretory environment guiding new immune responses. The early development of immune responses is regulated by multiple cytokines/chemokines acting together, which at physiologic concentrations act locally in concert with antigen to have non-specific effects on adjacent cells, including the maturation of dendritic cells, homing and retention of T cells at the site of antigen, and the differentiation and expansion of T cell clones with appropriate receptors. We postulated that repeated injections into a metastasis of an exogenous chemokine/cytokine mixture might establish the environment of an immune response and allow circulating T cell clones to self- select for mutant neo-epitopes in the tumor and generate systemic immune responses. To test this idea we injected some metastases in patients with multiple cutaneous melanoma nodules while never injecting other control metastases in the same patient. New immune responses were identified by the development of dense lymphocytic infiltrates in never-injected metastases, and the frequent complete regression of never-injected metastases, a surprising observation. 70% of subjects developed dense infiltrates of cytotoxic CD8 cells in the center and margin of never-injected metastases; 38% of subjects had complete and often durable regressions of all metastases, without the use of check-point inhibitors, suggesting that, as a proof-of-principle, an immunization strategy can control advanced human metastatic melanoma.

KEYWORDS:

• cancer vaccine
• CD8 T cells
• cytokines
• immunotherapy
• metastatic melanoma
• tumor infiltrating lymphocytes

Disclosures of potential conflicts of interest

No potential conflicts of interest were disclosed.

Acknowledgments

Laboratory experiments and preparation of patient cytokineswere conducted by Jin-Sheng Yao, Anna Maria Paolino and Vincenza Itri. Histopathology for this study was performed by Dr. A. Bernard Ackerman. We thank Drs. James Speyer and Ruth Oratz, Medical Oncologists, who also followed patients during the study and cared for the many patients who did not respond to cytokines. We also thank Dr. Speyer for suggestions on the design of the manuscript. We are grateful to the patients who participated in this study, often over several years

Funding

This work was initially supported by the National Cancer Institute CA 19529 (FTV), and also supported by the Fan Fox and Leslie Samuels Foundation, Friends of Caroline, and the Cancer Surgery Research Fund. Clinical visits were conducted in the General Clinical Research Center: current grant UL1TR000038.

Author's contributions

Conception and design: F.V, F.G, M.H., D.R.

Director of Study: F.V.

Acquisition of patient data and biopsies: F.G, D.R, M.H.

Laboratory studies: F.V.

Analysis and interpretation of data: F.V, F.G, D.R

Writing of manuscript: F.V.

Review of manuscript: F.V, D.R, M.H, F.G