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Genetic changes occurring in established tumors rapidly stimulate new antibody responses.

ABSTRACT: Cancer patients and tumor-bearing mice possess serum antibodies that recognize antigens expressed by cancer cells at the time of diagnosis. After diagnosis, cancers progress to more aggressive stages, most often by acquiring new genetic changes that can give rise to new proteins, some of which are antigenic. However, at these relatively later stages of tumor growth, it remains unclear whether, when, and how a host can generate de novo antibody responses against these newly appearing tumor antigens. To this end, we used a tamoxifen-regulated Cre-loxP system, MerCreMer, to induce genetic recombination in cancer cells of well-established tumors, resulting in increased enhanced green fluorescence protein (EGFP) expression. These late tumor-bearing mice generated specific IgG antibodies against EGFP within 3 wk after antigen induction. Mice generated these antibody responses in the presence of preexisting anti-tumor antibody responses. Preexisting CD4(+) T cell responses to already expressed tumor antigens likely enhanced antibody responses to the induced EGFP antigen. By analogy, new antibody responses in cancer patients may identify genetic changes occurring in a growing tumor and indicate imminent tumor progression.

SUBMITTER: Spiotto MT

PROVIDER: S-EPMC154361 | biostudies-literature | 2003 Apr

REPOSITORIES: biostudies-literature

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Genetic changes occurring in established tumors rapidly stimulate new antibody responses.

Spiotto Michael T MT Reth Michael A MA Schreiber Hans H

Proceedings of the National Academy of Sciences of the United States of America 20030417 9

Cancer patients and tumor-bearing mice possess serum antibodies that recognize antigens expressed by cancer cells at the time of diagnosis. After diagnosis, cancers progress to more aggressive stages, most often by acquiring new genetic changes that can give rise to new proteins, some of which are antigenic. However, at these relatively later stages of tumor growth, it remains unclear whether, when, and how a host can generate de novo antibody responses against these newly appearing tumor antige ...[more]

PMID: 12702750

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Project description:Regulatory T cells (Tregs) contribute to an immunosuppressive tumor microenvironment. They play an important role in the establishment and progression of tumors with high Tregs infiltration and present a major obstacle to tumor eradication by immunotherapies. Numerous strategies have been attempted to deplete or block Tregs, although their success has been limited. A CD25-targeted, pyrrolobenzodiazepine (PBD) dimer-based antibody-drug conjugate (ADC) was investigated for its ability to deplete Tregs and induce antitumor immunity. Antitumor activity of CD25-ADC either alone or in combination with an anti-programmed cell death protein 1 (PD-1) antibody was evaluated in CD25-negative syngeneic models that exhibit tumor infiltration of CD25-expressing Tregs, and its pharmacodynamics and pharmacokinetics were assessed. Single low doses of CD25-ADC resulted in potent and durable antitumor activity in established syngeneic solid tumor models and the combination of a suboptimal dose was synergistic with PD-1 blockade. Tumor eradication by the CD25-targeted ADC was CD8+ T cell-dependent and CD25-ADC induced protective immunity. Importantly, while CD25-ADC mediated a significant and sustained intratumoral Tregs depletion, accompanied by a concomitant increase in the number of activated and proliferating tumor-infiltrating CD8+ T effector cells, systemic Tregs depletion was transient, alleviating concerns of potential autoimmune side effects. This study shows that a PBD dimer-based, CD25-targeted ADC is able to deplete Tregs and eradicate established tumors via antitumor immunity. This represents a novel approach to efficiently deplete Tregs via a very potent DNA damaging toxin known to induce immunogenic cell death. Moreover, this study provides proof of concept for a completely new application of ADCs as immunotherapeutic agents, as the main mode of action relies on the ADC directly targeting immune cells, rather than tumor cells. These strong preclinical data warrant the clinical evaluation of camidanlumab tesirine (ADCT-301), a PBD-based ADC targeting human CD25, either alone or in combination with checkpoint inhibitors in solid tumors with known Tregs infiltration. A phase I trial (NCT03621982) of camidanlumab tesirine in patients with selected advanced solid tumors is ongoing.

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Genetic changes occurring in established tumors rapidly stimulate new antibody responses.

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Genetic changes occurring in established tumors rapidly stimulate new antibody responses.

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