During cancer immunoediting, loss of major histocompatibility complex class I (MHC-I) in neoplasm contributes to the evasion of tumours from host immune system. Recent studies have demonstrated that most natural killer (NK) cells that are found in advanced cancers are defective, releasing the malignant MHC-I-deficient tumours from NK-cell-dependent immune control. Here, we show that a natural killer T (NKT)-cell-ligand-loaded tumour-antigen expressing antigen-presenting cell (APC)-based vaccine effectively eradicates these advanced tumours. During this process, we find that the co-expression of Tim-3 and PD-1 marks functionally exhausted NK cells in advanced tumours and that MHC-I downregulation in tumours is closely associated with the induction of NK-cell exhaustion in both tumour-bearing mice and cancer patients. Furthermore, the recovery of NK-cell function by IL-21 is critical for the anti-tumour effects of the vaccine against advanced tumours. These results reveal the process involved in the induction of NK-cell dysfunction in advanced cancers and provide a guidance for the development of strategies for cancer immunotherapy.
BVAC-C is a B cell-based and monocyte-based immuno-therapeutic vaccine transfected with a recombinant human papillomavirus (HPV) 16/18 E6/E7 gene and loaded with alpha-galactosyl ceramide, which is a natural killer T cell ligand. This phase I study sought to determine the tolerability and immunogenicity of BVAC-C in platinum-resistant recurrent cervical cancer patients. Patients with HPV 16-positive or 18-positive recurrent or persistent cervical cancer who had received at least one prior platinum-based combination chemotherapy were enrolled. BVAC-C was injected intravenously three times every four weeks, and dose escalation was planned in a three-patient cohort design at doses of 1 × 107, 4 × 107, or 1 × 108 cells/dose. Eleven patients were enrolled, and six (55%) patients had received two or more lines of platinum-based chemotherapy prior to enrollment. Treatment-related adverse events (TRAEs) were observed in 21 cycles. Most TRAEs were mild fever (n = 6.55%) or myalgia (n = 4.36%). No dose-limiting toxicities occurred. The overall response rate was 11% among nine patients evaluable, and the duration of response was 10 months. Five patients (56%) achieved a stable disease for 4.2–11 months as their best overall response. The median progression-free survival in all patients was 6.8 months (95% CI, 3.2 to infinite months), and the overall survival rate at 6 and 12 months was 89% (95% CI, 71 to 100%) and 65% (95% CI, 39 to 100%), respectively. BVAC-C induced the activation of natural killer T cells, natural killer cells, and HPV 16/18 E6/E7-specific T cells upon vaccination in all patients evaluated. BVAC-C was well tolerated and demonstrated a durable anti-tumor activity with an immune response in HPV 16-positive or 18-positive recurrent cervical carcinoma patients. A Phase 2 efficacy trial is currently underway.
IntroductionLangerhans cell histiocytosis (LCH) occurs rarely in the spine of adults. The radiological findings usually resemble vertebral tumors. Etiology of LCH has not been clearly established yet. Therapeutic approaches are still controversial. We describe a case of LCH in an adult spine.Case descriptionA patient who presented with low back pain had an osteolytic lesion in the L1 vertebral body without neurological deficits, and fluoroscopy-guided needle biopsy of the L1 vertebral body was performed. The immunohistochemical diagnosis confirmed LCH. The patient was successfully treated with conservative methods.DiscussionThe choice of appropriate therapy is very important, with treatment options varying from watch-and to aggressive treatment.ConclusionLCH is considered as a pediatric disease that is extremely rare in the spine of adults and should be include in the differential diagnosis of osteolytic vertebral lesions. Conservative treatment is best choice for a patient with LCH without neurological deficit or spinal instability.
4534 Background: BVAC-B is an autologous B cell- and monocyte-based immunotherapeutic vaccine transfected with recombinant HER2/neu gene and loaded with alpha-galactosyl ceramide, a natural killer T cell ligand. It may have activity against HER2/neu positive cancer. Preclinical data in mouse models have shown promising anti-tumor activity by eliciting broad spectrum of immune responses against HER2/neu positive tumor cells. We report here the results of phase 1 study of BVAC-B in HER2 positive advanced gastric cancer. Methods: Metastatic gastric cancer with IHC > 1+ of HER2/neu were eligible for enrollment. Two weeks before treatment, subjects were admitted to hospital for collection of PBMC and plasma by lymphapheresis. The PBMC were sent to Cellid for vaccine manufacturing which took a day. BVAC-B was given intravenously at 0, 4, 8, and 12 weeks. Subjects received low (2.5X 107 cells/dose), medium (5.0X 107 cells/dose) or high dose (1.0X 108 cells/dose). Endpoints included safety, tolerability and MTD for phase 2 trial. Exploratory outcomes included immune responses after BVAC-B administration. Results: As of January 29, 2020, 8 subjects were treated with BVAC-B at doses of 2.5X 107 cells/dose (n=1), 5.0X 107 cells/dose (n=1) and 1.0X 108 cells/dose (n=6). Median line of therapy at which BVAC-B was administered was 4 (range, 2-9). Mean duration treatment was 1.8 (range 1-4) cycles. The most common treatment related adverse events were fever (n=4, 50%). One subject enrolled in medium dose experienced cytokine release syndrome (G2) with high fever (39.3℃) and hypotension 8 hours after first administration, but was manageable with hydration and supportive management. Other adverse events included increase of AST and ALT (G1, n=1 and G2, n=2), and hypotension (G1, n=1). There were no adverse events which led to treatment discontinuation. Immunologic response analysis showed that BVAC-B induced activation of natural killer T cells, natural killer cells, HER2/neu specific T cells, and release of HER2/neu specific antibody upon vaccinations in few patients who were evaluated. Conclusions: BVAC B is feasible and has acceptable toxicity profile. We considered all dose evaluated in this study available for phase 2 study, given that the maximum tolerated dose is expected to exceed the maximum dose administered in this study. For clinically relevant effect, further studies are warranted, including earlier line of exposure to BVAC-B as well as combination treatments. Clinical trial information: NCT03425773 .
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