A phase II study of adoptive immunotherapy using dendritic cells pulsed with tumor lysate in patients with hepatocellular carcinoma

Palmer, Daniel H.; Midgley, Rachel; Mirza, Noweeda; Torr, Elizabeth; Ahmed, Fahim; Steele, Jane C.; Steven, Neil; Kerr, David J.; Young, Lawrence S.; Adams, David H.

doi:10.1002/hep.22626

Cited by 249 publications

(167 citation statements)

References 78 publications

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“…38 However, for the successful development of peptide-based immune therapies, it will be important to identify dominant AFP-specific CD4þ T-cell epitopes, as until now only a few such epitopes have been identified. 18,39 In our study, we were unable to detect a clear immunodominance of the CD4þ T-cell responses that were spread across the entire AFP protein.…”

Section: Tumor Immunologymentioning

confidence: 99%

Lack of ex vivo peripheral and intrahepatic α‐fetoprotein‐specific CD4+ responses in hepatocellular carcinoma

Witkowski

Spangenberg

Büttner

et al. 2011

Intl Journal of Cancer

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Hepatocellular carcinoma (HCC) is one of the most common malignancies with a poor prognosis and limited therapeutic options that is often characterized by the expression of the tumor-associated antigen a-fetoprotein (AFP). CD41 helper T cells are important in generating potent anticancer immunity as they prime and expand CD81 T-cell memory and may also have direct antitumor activity. However, very little information is currently available about the relative frequency, immunodominance and peripheral versus intratumoral distribution of AFP-specific CD41 T-cell responses in patients with HCC. We, therefore, analyzed AFP-specific CD41 responses in blood and tumor tissue of patients with HCC by using overlapping peptides spanning the entire AFP protein and novel sensitive approaches such as antigen-specific upregulation of CD154. We found that AFP-specific CD41 T-cell responses were not detectable in the peripheral blood ex vivo. However, after in vitro stimulation, AFP-specific CD41 T-cell responses were detectable in a large fraction of patients targeting different previously unreported epitopes with no clear immunodominance. These results indicate that AFP-specific CD41 T-cell responses are not completely deleted but only present at very low frequencies. Importantly, AFP-specific CD41 T-cell responses were also rarely detectable in tumor tissue, suggesting that the relative absence of these cells in the circulation ex vivo is not due to a rapid accumulation to the tumor side. Taken together, these results suggest that the lack of sufficient CD41 T-cell help, especially within the tumor tissue, may be one central mechanism responsible for the failure of AFP-specific immune responses to control HCC progression.Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide with a poor prognosis and limited therapeutic options. Therefore, the development of novel therapeutic strategies is of high priority. Immunotherapy represents a promising potential option for several reasons: First, a correlation has been reported between high numbers of tumor-infiltrating T cells in HCC tissue and the prognosis of disease.1,2 Second, adoptive immunotherapy with anti-CD3-and interleukin-2-stimulated autologous lymphocytes lowers postsurgical HCC recurrence rates in humans.3 Finally, the induction of anti-a-fetoprotein (AFP) cell-mediated immune responses can control tumor growth in the mouse model. 4AFP is a serum marker for HCC that is elevated in 50-80% of patients with HCC. Physiologically, AFP is highly expressed in fetal liver, gastrointestinal tract and yolk sac but is transcriptionally downregulated after birth. Importantly, after birth, AFP can be elevated in patients with HCC or testicular cancers.5 Of note, this can be associated with the emergence of AFP-specific immune responses. For example, several human leukocyte antigen (HLA) class I-restricted AFP-specific epitopes have been identified by different approaches and shown to be present in HCC patients. [6][7][8][9] Indeed, in a recent comprehensive anal...

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Section: Tumor Immunologymentioning

confidence: 99%

Lack of ex vivo peripheral and intrahepatic α‐fetoprotein‐specific CD4+ responses in hepatocellular carcinoma

Witkowski

Spangenberg

Büttner

et al. 2011

Intl Journal of Cancer

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“…Among the different approaches, immune checkpoints blockade has disclosed promising results, as long as treatment with these molecules has shown an objective radiological response with an acceptable security profile. The potential benefit of this approach should be confirmed in larger, randomized trials (121,122). All these efforts will allow, in an immediate future, increasing therapeutic options for our HCC patients at advanced stage.…”

Section: Improvements In the Treatment Of Intermediate-advanced Hccmentioning

confidence: 95%

New challenges in clinical research on hepatocellular carcinoma

Díaz-González¹,

Forner²,

C³

et al. 2015

Rev Esp Enferm Dig

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This is an updated review of screening, early diagnosis and treatment of hepatocellular carcinoma, focusing on the advancements occurred in the last years and highlighting the challenges in clinical research.Hepatocellular carcinoma (HCC) is nowadays the sixth most frequent cancer worldwide with up to 740,000 new cases diagnosed each year, and it is the third most prevalent cause of cancer-relateddeath worldwide (1). This neoplasm usually appears linked to an underlying liver disease, being one of the most relevant causes of death in patients diagnosed of liver cirrhosis (2,3). In the last years, important advancements in terms of diagnosis, staging and treatment of HCC, improving the management and outcome of the disease, have been made (4-7). Despite the fact that these improvements have absolutely changed natural history of HCC, there are several areas that still need further advancements.The aim of this document is to discuss some controversial aspects, which in our opinion constitute real challenges in clinical research of HCC.Key words: Hepatocellular carcinoma. Hepatic oncology. Sorafenib. Transarterial chemoembolization. AFP. IMPROVING EARLY DIAGNOSISFrom the basis that the only possibility to offer and apply treatments with curative intention is being able to diagnose HCC at early stages, when there are not cancer related symptoms. Since this option is only feasible if screening is performed in population at risk, scientific guidelines recommend performing abdominal ultrasonography (US) in every patient with liver cirrhosis. Despite the recommendation of HCC screening by the Spanish guidelines (4), one registry study performed in Spain which included 62 centers and 705 patients diagnosed of HCC within a period of time of 4 months showed that just 47% of HCC patients were diagnosed in the setting of surveillance and less than a half were diagnosed at early stage (8).This data shows that early diagnosis, a key issue to be able to significantly reduce HCC-related mortality, is one of the most relevant issues that deserve further efforts from scientific community. Aiming to evaluate which were the causes of screening program fail in the United States of America, Singal et al. evaluated 1,005 patients included in the HALT-C prospective study. A third part of patients did not adhere to an adequate screening program and, in 70% of cases that were diagnosed at an advanced stage, the main reason was the absence of detection in US (9).With the aim of improving detection rate, it is crucial to establish formative programs in order to certify the capability of being able to carry on this activity and it is necessary to use up-to-date ultrasonography scans in order to perform an optimal liver exploration. Tumor markers could be a useful tool to overcome theoretical limitations of US: its evaluation is not subjective, does not depend on the operator and it may be reproducible, as well as it is relatively cheap and a tool easy to access in areas with low monetary income. Regrettably, different tumor markers ev...

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“…3 Dendritic cells (DCs) are potent professional APCs that can capture, process and present antigens. Additionally, they are critical for exerting T-cell-mediated immune responses, activating naïve T cells and playing a critical role in innate immune response and adaptive immune response.…”

Section: Background and Aimsmentioning

confidence: 99%

Phase Ⅰ clinical study of combination therapy with microwave ablation and cellular immunotherapy in hepatocellular carcinoma

Zhou

Liang²,

Dong³

et al. 2011

Cancer Biology & Therapy

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Percutaneous ablation therapy has been widely accepted as one of the radical treatment methods for small hepatocellular carcinoma (HCC) and the 5-year survival rate is similar to that obtained by resection. 1 The search for new and effective methods to prolong the overall survival and disease-free survival time requires further advances. HCC is a potential target for immunotherapy, as evidenced by an active recruitment of tumor-infiltrating lymphocytes (TIL) that display antitumor cytolytic activity in the presence of interleukin (IL) 2 in ex vivo studies.2 However, TIL in HCC are of dysfunction, few in quantity and do not kill tumor cells, which suggests that immunosuppressive mechanisms prevent T cells from maturing into effective antitumor effectors. The activation of tumor-specific cytotoxic T lymphocytes (CTL) requires three synergistic signals: the presentation of tumor antigen by antigen-presenting cells (APC) to specific T-helper cells; the interaction between costimulatory factors (such as B7.1 and CD28 ligand); Background and Aims: To observe safety and influence on viral load and peripheral T-lymphocyte subsets of combination therapy with percutaneous microwave ablation (PMWa) and adoptive immunotherapy in hepatocellular carcinoma (HCC) with hepatitis B.Results: no adverse effects of grade iii/iV were observed. Viral load was decreased in 57.14% (four of seven) of patients and was undetectable in two (28.6%) patients without antiviral therapy. The percentage of Cd4 + Cd25 high regulatory T lymphocytes decreased significantly and the percentage of Cd8 + Cd28 -effector cells increased significantly 1 month after therapy. However, 6 months after therapy, there was no significant difference.Methods: Ten HCC (d ≤5 cm, fewer than three tumors) patients were treated with radical PMWa and three courses of immunotherapy, which were started with PMWa, 2 weeks post-PMWa and 3 months after PMWa. Peripheral blood mononuclear cells were differentiated into phenotypically confirmed dCs and effector cells. immature dCs, cytokineinduced killer cells (CiK) and cytotoxic T lymphocytes (CTL) were injected into the marginal area of ablated tumors under contrast-enhanced sonographic guidance. under sonographic guidance, tumor lysate-pulsed dC was injected into groin lymph nodes, while dC-CiK and CTL were injected into the abdominal cavity. CiK was infused intravenously.Conclusion: adoptive immunotherapy prescribed soon after PMWa for HCC patients was safe and ameliorated the percentage of peripheral lymphocytes.

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A phase II study of adoptive immunotherapy using dendritic cells pulsed with tumor lysate in patients with hepatocellular carcinoma

Cited by 249 publications

References 78 publications

Lack of ex vivo peripheral and intrahepatic α‐fetoprotein‐specific CD4+ responses in hepatocellular carcinoma

Lack of ex vivo peripheral and intrahepatic α‐fetoprotein‐specific CD4+ responses in hepatocellular carcinoma

New challenges in clinical research on hepatocellular carcinoma

Phase Ⅰ clinical study of combination therapy with microwave ablation and cellular immunotherapy in hepatocellular carcinoma

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