Personalized neoantigen-based immunotherapy for advanced collecting duct carcinoma: case report

Abstract

Background: Collecting duct carcinoma (CDC) of the kidney is a rare and highly aggressive malignant tumor with the worst prognosis among all renal cancers. Nevertheless, the first-line treatments, including chemotherapy and target therapy, usually show poor response to CDC. Recent studies have suggested that immunotherapy targeting personal tumor-specific neoantigens could be a promising strategy for several solid cancers. However, whether it has therapeutic potential in CDC remains unclear.

Case presentation: Here, we report a case of an Asian patient who underwent personalized neoantigen-based immunotherapy. The patient was diagnosed with metastatic CDC and suffered extensive tumor progression following sorafenib treatment. Based on the patient's own somatic mutational profile, a total of 13 neoantigens were identified and corresponding long-peptide vaccine and neoantigen-reactive T cells (NRTs) were prepared. After six cycles of neoantigen-based vaccination and T-cell immunotherapy, the patient was reported with stable disease status in tumor burden and significant alleviation of bone pain. Ex vivo interferon-γ enzyme-linked immunospot assay proved the reactivity to 12 of 13 neoantigens in peripheral blood mononuclear cells collected after immunotherapy, and the preferential reactivity to mutant peptides compared with corresponding wild-type peptides was also observed for 3 of the neoantigens. Surprisingly, biopsy sample collected from CDC sites after 3 months of immunotherapy showed decreased mutant allele frequency corresponding to 92% (12/13) of the neoantigens, indicating the elimination of tumor cells carrying these neoantigens.

Conclusions: Our case report demonstrated that the combined therapy of neoantigen peptide vaccination and NRT cell infusion showed certain efficacy in this CDC case, even when the patient carried only a relatively low tumor mutation burden. These results indicated that the personalized neoantigen-based immunotherapy was a promising new strategy for advanced CDC.

Trial registration number: ChiCTR1800017836.

Keywords: immunology; tumors.

Figure 1

Diagnostic assessment, treatment, and clinical monitoring of the patient with CDC. (A) Pretreatment assessment of primary CDC tumor and bone metastasis lesion, as determined by pathological examination of H&E-stained needle biopsies. (B) Timeline presentation of the treatment dates of personalized neoantigen peptide vaccination and NRT infusion. (C, D) Timeline of kidney and lumbar vertebra CT scans and the corresponding tumor size during neoantigen-based immunotherapy. The red arrows indicate the primary tumor lesion (upper panel) and metastatic tumor lesions (lower panel). CDC, collecting duct carcinoma; NRT, neoantigen-reactive T cell.

Figure 2

Monitoring of the neoantigen-induced peripheral blood T-cell responses. PBMCs collected at the time points of preimmunotherapy and postimmunotherapy were assessed for neoantigen-specific T-cell responses. (A) Comparison of IFN-γ secretion by PBMCs from preimmunotherapy and postimmunotherapy time point stimulated by neoantigen pools. (B) Images of IFN-γ secretion of PBMCs stimulated by each neoantigen (CCNA1, LIPE and KRAS) comparing with their corresponding wild-type peptides. (C) Quantitative results of IFN-γ secretion by PBMCs against autologous dendritic cells which presented 13 neoantigens individually comparing with their corresponding wild-type peptides. (D) Activated T-cell percentage (CD3⁺/4-1BB⁺ cell population) in neoantigen-reactive T-cell preparation. IFN, interferon; PBMC, peripheral blood mononuclear cell.

Figure 3

Immune signatures in CDC biopsies collected at preimmunotherapy and postimmunotherapy time point. (A) Mutated allele frequency of the 13 neoantigens in CDC tissues collected preimmunotherapy and postimmunotherapy. (B) Clonal evolution of tumor tissues collected preimmunotherapy and postimmunotherapy. Neoantigens were indicated by solid circles. (C, D) Change tendency of costimulatory signals and coinhibitory signals after immunotherapy. (E, F) Immunophenogram calculated according expression profiles of CDC biopsies collected at preimmunotherapy (left) and postimmunotherapy (right) time points. MHC molecules (MHC), immunomodulators (CP), ECs and SCs. CDC, collecting duct carcinoma; CP, checkpoint; EC, effector cell; MHC, major histocompatibility complex; SC, suppressor cell.