Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial

Takayama, Tadatoshi; Sekine, Teruaki; Makuuchi, Masatoshi; Yamasaki, Susumu; Kosuge, Tomoo; Yamamoto, Junji; Shimada, Kazuaki; Sakamoto, Michiie; Hirohashi, Setsuo; Ohashi, Yasuo; Kakizoe, Tadao

doi:10.1016/s0140-6736(00)02654-4

Cited by 810 publications

(621 citation statements)

References 26 publications

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“…Ueda et al have reported an efficacy of AIT using LAK cells for metastatic esophageal cancer (14). The clinical trials using postoperative LAK cell transfer have demonstrated survival benefits in hepatocellular carcinoma (15) and lung cancer (16). However, the effects of AIT using LAK cells for postoperative stress status, SIRS and CARS have not yet been demonstrated.…”

Section: Introductionmentioning

confidence: 99%

Postoperative immunosuppression cascade and immunotherapy using lymphokine-activated killer cells for patients with esophageal cancer: Possible application for compensatory anti-inflammatory response syndrome

Yamaguchi

Hihara²,

Hironaka³

et al. 2006

Oncol Rep

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Abstract.Immunological parameters were measured in order to elucidate a postoperative immunosuppression mechanism in transthoracic esophagectomy for patients with esophageal cancer. Moreover, lymphokine-activated killer (LAK) cells were transferred just after the surgery to overcome the postoperative immunosuppression. Fifteen consecutive patients who underwent transthoracic esophagectomy were subjected to the postoperative measurement of immunological parameters. Ten patients who underwent open cholecystectomy served as controls. Heparinized venous blood was obtained pre-and postoperatively, and serum levels of cytokines IL-6 and IL-10 and immunosuppressive acidic protein (IAP) were measured. Peripheral blood lymphocytes were harvested and analyzed by flow cytometry for phenotype detection and by a mixed lymphocyte reaction for detecting concanavalin (Con)-A-induced or -non-induced suppressor activity. Another 29 consecutive patients who underwent transthoracic esophagectomy were randomly enrolled in a postoperative immunotherapy trial either with or without lymphokineactivated killer cells. It was found that, in the esophagectomy group, IL-6 and IL-10 increased postoperatively and peaked on day 1, followed by an increase in IAP, peaked again on day 4, with a profound decrease in helper and cytotoxic T-cell subsets, followed by increases in Con-A-induced (on day 7 or later) and spontaneous (on day 10) suppressor activities. These changes were minimal in the cholecystectomy group. LAK cell transfer restored the postoperative decrease in the helper and cytotoxic T-cell population, and there was a trend of reduction for postoperative remote infection such as pneumonia and surgical site infection in the LAK therapy group. Taken together, we would like to propose the existence of a postoperative immunosuppression cascade consisting of increases in cytokines and immunosuppressive proteins, decreases in helper and cytotoxic T-cell populations, and the development of suppressor T-cell activities in surgery for esophageal cancer. Postoperative adoptive transfer of LAK cells may be a novel clinical application in surgery for esophageal cancer as a means of treating this postoperative immunosuppressive condition that may be identical to the status of compensatory anti-inflammatory response syndrome (CARS).

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Section: Introductionmentioning

confidence: 99%

Postoperative immunosuppression cascade and immunotherapy using lymphokine-activated killer cells for patients with esophageal cancer: Possible application for compensatory anti-inflammatory response syndrome

Yamaguchi

Hihara²,

Hironaka³

et al. 2006

Oncol Rep

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“…40 It is plausible that the sole injection of LAK cells in lymphatic vessels could activate a similar clinical response.…”

Section: Discussionmentioning

confidence: 99%

Immunotherapy of metastatic kidney cancer

et al. 2001

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, 122 MRCC patients were treated by monthly intralymphatic injections (containing a mean of 573 IL-2 U and 26 ؋ 10 6 LAK cells) and i.m. administration of IFN and TF; 71 patients also received a 3-day cycle of monthly IL-2 inhalations with a mean of 998 daily U. MRCC cases not treated by immunotherapy (n ‫؍‬ 89) represent our historical controls. Adverse clinical side effects related to treatment were negligible. CR (n ‫؍‬ 11) and PR (n ‫؍‬ 13) were noticed in 24/122 patients. Of 24 responding patients, 17 resumed progression, whereas 7 remain in remission 11-69 months later. The overall median survival of treated patients (28 months) was 3.5-fold higher than the median survival of historical controls (7.5 months), and a Kaplan-Meier curve showed 25% survival 11 years after the beginning of immunotherapy. Apparently, the addition of IL-2 by inhalation improved survival. The present immunotherapy protocol appears to be efficacious, safe, devoid of adverse side effects, far less costly than others and able to offer a good quality of life to MRCC patients; if confirmed in a multicenter trial, it could set the basis for developing lowdose immunomodulatory treatments. © 2001 Wiley-Liss, Inc. Key words: immunotherapy; IL-2; lymphokine-activated killer cells; metastasis; transfer factor; interferon; renal cancerThe most promising systemic therapy for MRCC is immunotherapy with IL-2. 1 The original observations by Rosenberg et al., 2 using i.v. administration of high-dose rIL-2 and LAK in MRCC patients showed encouraging clinical response rates and longlasting remissions. These results have prompted many clinical trials using various administration routes: i.v. both in bolus and continuous or s.c. in combination or not with IFN and/or chemotherapeutic agents. In 1,411 MRCC patients, the overall rate of response was 20%. 3,4 Nonetheless, despite the lowering of the IL-2 dosage and the decrease of the 4% fatal outcome of the initial studies, thanks to the improved selection of patients and the clinical experience acquired, 5,6 the persistence of more often than not severely adverse clinical side effects remains the most important hindrance for the wide use of IL-2.Hence, being aware of the risk from a high IL-2 dose and of its ability to activate, at low doses, tumor mass rejection, 7-9 we attempted to develop alternative protocols. An observation made in 1 MRCC patient, in whom injection of a metastasis with IL-2 and LAK cells was followed by regression not only of the treated tumor but also of several other abdominal lymph node metastases, prompted us to further investigate the low-dose effect using the intralymphatic route. Following intratumor low-dose injections of IL-2 into infiltrating bladder cancers or lymph node metastases of MRCC patients, both the injected and the non-injected distant metastases often disappeared. 7,8 Thus, by administering very low doses of IL-2 and LAK cells into the lymphatic vessels of the foot, we observed encouraging clinical results with minimal side effects. 10,11 To boost the overall ...

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“…Therefore, all these data underscore, from a practical point of view, the need for adjuvant therapy (tertiary prevention) in the effort to prolong survival and reduce recurrence rates. In the past, different anticancer agents have been evaluated for tertiary prevention of HCC recurrence, including retinoids [42], intra-arterial I-131 [43], adoptive immunotherapy [44], and finally IFN [45][46][47][48][49]. Recently, sorafenib, an oral multi-kinase inhibitor targeting both tumor cells and the tumor vasculature is being evaluated in the setting of tertiary chemoprevention.…”

Section: Tertiary Chemopreventionmentioning

confidence: 99%

Does chemotherapy prevent HCV-related hepatocellular carcinoma? Cons

Craxı̀¹,

Cammà²

2010

Digestive and Liver Disease

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The accuracy and the reliability of well-recognized clinical, virologic, histologic, and molecular risk factors for hepatocellular carcinoma (HCC) are still insufficient. Thus, accurate risk prediction of cancer development in individual patients with the aim of selecting high risk cohorts of patients for HCC chemoprevention programs remains an elusive goal. Future directions in chemoprevention of HCC will be in the development of molecular risk models and of new chemopreventive agents. Studies examining multiple genes and proteins (genomics and proteomics) in the same HCCs will be required to evaluate this possibility thoroughly. A strategy aiming at preventing chronic liver disease of any etiology (HCV and HBV infection, alcohol, obesity, others) may be required to prevent HCC in low and intermediate incidence areas, and hence, worldwide. In the setting of secondary chemoprevention, literature data pooling suggests a slight preventive effect of interferon (IFN) on HCC development in patients with HCV-related cirrhosis. The magnitude of this effect is low, and the observed benefit might be due to spurious associations. The preventive effect is limited to sustained virological responders to IFN. So, there is no sound evidence to support a recommendation for widespread use of IFN to prevent HCC in HCV-related cirrhosis. In the setting of tertiary chemoprevention, the risk of recurrence of HCC may be reduced by IFN treatment in selected patient populations. Further large-scale multicenter randomized controlled trials may prove useful to evaluate the benefit on overall survival.

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Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomised trial

Cited by 810 publications

References 26 publications

Postoperative immunosuppression cascade and immunotherapy using lymphokine-activated killer cells for patients with esophageal cancer: Possible application for compensatory anti-inflammatory response syndrome

Postoperative immunosuppression cascade and immunotherapy using lymphokine-activated killer cells for patients with esophageal cancer: Possible application for compensatory anti-inflammatory response syndrome

Immunotherapy of metastatic kidney cancer

Does chemotherapy prevent HCV-related hepatocellular carcinoma? Cons

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