Phase I/II study of adjuvant immunotherapy with sentinel lymph node T lymphocytes in patients with colorectal cancer

Zhen, Yunhuan; Lu, Xiaohui; Yang, Yuan; Li, Bo; Tang, Jingling; Zeng, Qiang-Xing; Hu, Jie; Zeng, Xing-nan; Zhang, Lu; Wang, Zejun; Li, Xiaoyun; Ge, Hui-Xin; Winqvist, Ola; Hu, Peng; Xiu, Jin

doi:10.1007/s00262-015-1715-3

Cited by 45 publications

(39 citation statements)

References 46 publications

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“…Another ACT trial involving sentinel lymph node (SLN)-T cells instead of TILs was conducted in 16 and 55 CRC patients included in a pilot study and a phase I/II clinical trial, respectively. Encouragingly, 4 complete responses, 1 partial response and 4 cases of stable disease were observed in the 9 patients with stage IV CRC in each study (185,186). Other studies in CRC are currently ongoing (NCT03935893, NCT01174121, and NCT03904537) to confirm these preliminary results which suggest that ACT with TILs or SLN-T cells could benefit CRC patients, but also highlight a need for improvement of these therapies.…”

Section: Adoptive T-cell Therapy In Crcmentioning

confidence: 78%

Relationships Between Immune Landscapes, Genetic Subtypes and Responses to Immunotherapy in Colorectal Cancer

et al. 2020

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Colorectal cancer (CRC) is highly heterogeneous at the genetic and molecular level, which has major repercussions on the efficacy of immunotherapy. A small subset of CRCs exhibit microsatellite instability (MSI), a molecular indicator of defective DNA mismatch repair (MMR), but the majority are microsatellite-stable (MSS). The high tumor mutational burden (TMB) and neoantigen load in MSI tumors favors the infiltration of immune effector cells, and antitumor immune responses within these tumors are strong relative to their MSS counterparts. MSI has emerged as a major predictive marker for the efficacy of immune checkpoint blockade over the last few years and nivolumab or pembrolizumab targeting PD-1 has been approved for patients with MSI refractory or metastatic CRC. However, some MSS tumors show DNA polymerase epsilon (POLE) mutations that also confer a very high TMB and may also be heavily infiltrated by immune cells making them amenable to respond to immune checkpoint inhibitors (ICI). In this review we discuss the role of the different immune landscapes in CRC and their relationships with defined CRC genetic subtypes. We discuss potential reasons why immune checkpoint blockade has met with limited success for the majority of CRC patients, despite the finding that immune cell infiltration of primary non-metastatic tumors is a strong predictive, and prognostic factor for relapse and survival. We then consider in which ways CRC cells develop mechanisms to resist ICI. Finally, we address the latest advances in CRC vaccination and how a personalized neoantigen vaccine strategy might overcome the resistance of MSI and MSS tumors in patients for whom immune checkpoint blockade is not a treatment option.

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Section: Adoptive T-cell Therapy In Crcmentioning

confidence: 78%

Relationships Between Immune Landscapes, Genetic Subtypes and Responses to Immunotherapy in Colorectal Cancer

et al. 2020

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“…[9][10][11] Some investigators have used TDLNs as a source of T cells for adoptive T cell therapy and demonstrated their anti-tumor activity in clinical trials. 12,13 However, T cell repertoires in TDLNs have not been well characterized.…”

Section: Introductionmentioning

confidence: 99%

TCR sequencing analysis of cancer tissues and tumor draining lymph nodes in colorectal cancer patients

et al. 2019

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Tumor draining lymph nodes (TDLNs) are located in the routes of lymphatic drainage from a primary tumor and have the highest risk of metastasis in various types of solid tumors. TDLNs are also considered as a tissue to activate the antitumor immunity, where antigen-specific effector T cells are generated. However, T cell receptor (TCR) repertoires in TDLNs have not been well characterized. We collected 23 colorectal cancer tumors with 203 lymph nodes with/without metastatic cancer cells (67 were metastasis-positive and the remaining 136 were metastasis-negative) and performed TCR sequencing. Metastasis-positive TDLNs showed a significantly lower TCR diversity and shared TCR clonotypes more frequently with primary tumor tissues compared to metastasis-negative TDLNs. Principal component analysis indicated that TDLNs with metastasis showed similar TCR repertoires. These findings suggest that cancer-reactive T cell clones could be enriched in the metastasis-positive TDLNs. ARTICLE HISTORY

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“…Importantly, the procedure was reproducible as complete repeats of the stimulation procedures under research and under full GMP conditions showed similar results when compared to the first runs. Promising results already have been obtained in a pilot study in colorectal cancer patients, as immunotherapy or in adjuvant setting, using TDLN-expanded T cells for ACT [33, 34]. …”

Section: Discussionmentioning

confidence: 99%

Potential use of lymph node-derived HPV-specific T cells for adoptive cell therapy of cervical cancer

Poelgeest

Visconti

Aghai

et al. 2016

Cancer Immunol Immunother

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Adoptive transfer of tumor-specific T cells, expanded from tumor-infiltrating lymphocytes or from peripheral blood, is a promising immunotherapeutic approach for the treatment of cancer. Here, we studied whether the tumor-draining lymph nodes (TDLN) of patients with human papillomavirus (HPV)-induced cervical cancer can be used as a source for ACT. The objectives were to isolate lymph node mononuclear cells (LNMC) from TDLN and optimally expand HPV-specific CD4+ and CD8+ T cells under clinical grade conditions. TDLN were isolated from 11 patients with early-stage cervical cancer during radical surgery. Isolated lymphocytes were expanded in the presence of HPV16 E6 and E7 clinical grade synthetic long peptides and IL-2 for 22 days and then analyzed for HPV16 specificity by proliferation assay, multiparameter flow cytometry and cytokine analysis as well as for CD25 and FoxP3 expression. Stimulation of LNMC resulted in expansion of polyclonal HPV-specific T cells in all patients. On average a 36-fold expansion of a CD4+ and/or CD8+ HPV16-specific T cell population was observed, which maintained its capacity for secondary expansion. The T helper type 1 cytokine IFNγ was produced in all cell cultures and in some cases also the Th2 cytokines IL-10 and IL-5. The procedure was highly reproducible, as evidenced by complete repeats of the stimulation procedures under research and under full good manufacturing practice conditions. In conclusion, TDLN represent a rich source of polyclonal HPV16 E6- and E7-specific T cells, which can be expanded under clinical grade conditions for adoptive immunotherapy in patients with cervical cancer.Electronic supplementary materialThe online version of this article (doi:10.1007/s00262-016-1892-8) contains supplementary material, which is available to authorized users.

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Phase I/II study of adjuvant immunotherapy with sentinel lymph node T lymphocytes in patients with colorectal cancer

Cited by 45 publications

References 46 publications

Relationships Between Immune Landscapes, Genetic Subtypes and Responses to Immunotherapy in Colorectal Cancer

Relationships Between Immune Landscapes, Genetic Subtypes and Responses to Immunotherapy in Colorectal Cancer

TCR sequencing analysis of cancer tissues and tumor draining lymph nodes in colorectal cancer patients

Potential use of lymph node-derived HPV-specific T cells for adoptive cell therapy of cervical cancer

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