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Purpose: Genetically engineered T-cell therapy is an emerging treatment of hematologic cancers with potential utility in epithelial cancers. We investigated T-cell therapy for the treatment of metastatic human papillomavirus (HPV)-associated epithelial cancers.
Methods: This phase I/II, single-center trial enrolled patients with metastatic HPV16-positive cancer from any primary tumor site who had received prior platinum-based therapy. Treatment consisted of autologous genetically engineered T cells expressing a T-cell receptor directed against HPV16 E6 (E6 T-cell receptor T cells), a conditioning regimen, and systemic aldesleukin.
Results: Twelve patients were treated in the study. No dose-limiting toxicities were observed in the phase I portion. Two patients, both in the highest-dose cohort, experienced objective tumor responses. A patient with three lung metastases experienced complete regression of one tumor and partial regression of two tumors, which were subsequently resected; she has no evidence of disease 3 years after treatment. All patients demonstrated high levels of peripheral blood engraftment with E6 T-cell receptor T cells 1 month after treatment (median, 30%; range, 4% to 53%). One patient's resistant tumor demonstrated a frameshift deletion in interferon gamma receptor 1, which mediates response to interferon gamma, an essential molecule for T-cell-mediated antitumor activity. Another patient's resistant tumor demonstrated loss of , the antigen presentation molecule required for this therapy. A tumor from a patient who responded to treatment did not demonstrate genetic defects in interferon gamma response or antigen presentation.
Conclusion: Engineered T cells can induce regression of epithelial cancer. Tumor resistance was observed in the context of T-cell programmed death-1 expression and defects in interferon gamma and antigen presentation pathway components. These findings have important implications for development of cellular therapy in epithelial cancers.
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http://dx.doi.org/10.1200/JCO.18.02424 | DOI Listing |
J Clin Invest
December 2024
Department of Molecular Immunology, Research Institute for Microbial Diseas, Osaka University, Suita, Japan.
Mycobacterium tuberculosis causes human tuberculosis. As mycobacteria are protected by thick lipid cell wall, humans have developed immune responses against diverse mycobacterial lipids. Most of these immunostimulatory lipids are known as adjuvants acting through innate immune receptors, such as C-type lectin receptors.
View Article and Find Full Text PDFFront Immunol
December 2024
The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
This study explores a novel therapeutic strategy for relapsed/refractory (R/R) Burkitt lymphoma (BL) by integrating autologous hematopoietic stem cell transplantation (ASCT) with tandem anti-CD19/CD22 chimeric antigen receptor (CAR) T cell therapy. A 20-year-old Asian male with refractory BL, whose lymphoma had not responded to multiple chemoimmunotherapy regimens, received myeloablative ASCT followed three days later by infusion of a novel third-generation CAR T cells engineered with CD28 and CD3ζ signaling domains, along with a TLR2 costimulatory domain. This resulted in sustained complete remission at the 306-day follow-up, without experiencing any severe complications.
View Article and Find Full Text PDFImmunooncol Technol
December 2024
Programme in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore.
γδ T cells represent an 'unconventional' class of CD3+ lymphocytes with unique phenotypical and functional attributes that distinguishes them from their αβ T-cell receptor-expressing counterparts. Studies investigating the roles of γδ T cells in cancer have shown that these cells are indispensable for effective tumor control and their presence within the tumor may be of prognostic significance. Currently, there is significant interest in harnessing γδ T cells for cancer treatment, and research efforts have focused on the development of γδ T-cell-based strategies that are efficacious against cancer.
View Article and Find Full Text PDFJ Control Release
December 2024
Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Centre for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, People's Republic of China. Electronic address:
Self-adjuvanted vaccine delivery platforms possess potential for targeted delivery of antigens and initiation of potent immune responses. Although aluminum-containing adjuvants have been approved and widely used in human vaccines, their effectiveness in inducing Th1-type immune responses is far from satisfactory. To facilitate antigen delivery and activate potent antitumor immune responses, a self-adjuvanted nanovaccine (CPBG-Al@OVA) is constructed by functionalizing aluminum hydroxide with β-1,3-glucan, which recognizes pattern recognition receptors via Dectin-1.
View Article and Find Full Text PDFNat Biomed Eng
December 2024
Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Resistance to chimaeric antigen receptor (CAR) T cell therapy develops through multiple mechanisms, most notably antigen loss and tumour-induced immune suppression. It has been suggested that T cells expressing multiple CARs may overcome the resistance of tumours and that T cells expressing receptors that switch inhibitory immune-checkpoint signals into costimulatory signals may enhance the activity of the T cells in the tumour microenvironment. However, engineering multiple features into a single T cell product is difficult because of the transgene-packaging constraints of current gene-delivery vectors.
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