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Locoregional immuno(bio)therapy for liver metastases
Locoregional Immuno(bio)therapy for Liver Metastases Takami Sato Despite advances in locoregional chemotherapy, treatment of metastatic liver tumors remains a challenge. Since the liver is the largest organ of the reticuloendothelial system, locoregional immunotherapy would be a reasonable approach for the management of hepatic metastases. Indeed, various immunological approaches have been explored. Regional infusion of cytokines such as interleukin 2 (IL-2) or tumor necrosis factor-alpha (TNF-␣) through the hepatic artery or the portal vein has been combined with chemotherapy and demonstrated to be better than chemotherapy alone. Locoregional adaptive immunotherapy (AIT) using lymphokine-activated killer (LAK) cells or tumor-infiltrating lymphocytes (TIL) has also been tried with rather disappointing responses. Addition of immunostimulants such as OK-432 to AIT increased clinical responses. Recently, several new approaches have emerged to improve the outcome of locoregional immunotherapy. Embolization of melanoma metastatic to the liver with a granulocyte-macrophage colony-stimulating factor (GM-CSF)/ethiodized oil emulsion resulted in control of liver metastases, as well as development of significant immune responses in remote extrahepatic metastases. A gene therapy designed to introduce foreign major histocompatibility complex (MHC) molecules in colorectal metastases has proven to be a safe and feasible approach. Larger scale clinical trials are mandatory to define the role of locoregional immunotherapy for metastatic tumors in the liver. Semin Oncol 29:160-167. Copyright 2002, Elsevier Science (USA). All rights reserved.
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OCOREGIONAL immuno(bio)therapy for liver metastases offers several advantages over systemic immuno(bio)therapy: (1) direct administration of immune cells or immunostimulants into the tumor alters the environment within the tumor and may break immunotolerance elicited by tumor cells; (2) local administration of cytokines, such as interleukin-2 (IL-2), interferons (IFNs), or tumor necrosis factor alpha (TNF-␣), minimizes systemic toxicity; and (3) destruction of tumor cells in situ provides tumor antigens to the host immune system, which may result in a systemic immune response against tumor cells (in situ can-
From the Division of Medical Oncology, Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA. Address reprint requests to Takami Sato, MD, Division of Medical Oncology, Jefferson Medical College of Thomas Jefferson University, 1025 Walnut St, Suite 312, Philadelphia, PA 19107. Copyright 2002, Elsevier Science (USA). All rights reserved. 0093-7754/02/2902-0012$35.00/0 doi:10.1053/sonc.2002.31716 160
cer vaccine). Various locoregional immunological approaches have been developed, including intrahepatic infusion of cytokines combined with chemotherapy, adoptive immunotherapy with activated lymphocytes, or embolization of liver tumors with immunostimulants. Although the number of patients in each study is small and treatment modalities are variable, bonafide responses have been reported.1-4 These approaches would be especially useful in local control of unresectable, chemotherapy-resistant liver metastasis from melanoma, gastrointestinal malignancies, or breast cancer. RATIONALE FOR IMMUNO(BIO)THERAPY FOR LIVER METASTASES
One of the critical questions regarding local immunotherapy for liver metastasis is whether immunological responses can be induced in the liver. In this regard, the liver is the largest organ of the reticuloendothelial system and would be the appropriate target for immunotherapy. The liver contains more than 70% of all tissue macrophages (Kupffer cells) and eliminates bacteria and foreign bodies from the circulation. The liver responds rapidly to inflammation, as a secondary response to proinflammatory cytokines including IL-1, TNF-␣, and IL-6. In addition, hepatic sinusoidal lymphocytes (HSL), originally referred to as pit cells, have functions of natural killer (NK) cells.5 NK T cells and CD3⫹ ␥␦ T cells are also present in the liver.6 It has been reported that these immune cells in the liver can be activated by various cytokines including IL-2 and IFN-␥ and demonstrate antitumor activities.7,8 Since only 20% of patients with metastasis would be candidates for complete surgical resection9 and the majority of these patients will subsequently develop a local or systemic recurrence after local treatments of liver metastases,10-12 a new treatment modality to control local disease and to prevent systemic progression is needed. In this respect, locoregional immuno(bio)therapy is an attractive and reasonable approach for the management of liver metastasis. REGIONAL TREATMENT WITH BIOLOGICAL RESPONSE MODIFIERS
Systemic administration of biological response modifiers (BRM) produces durable responses in limited number of patients with chemotherapySeminars in Oncology, Vol 29, No 2 (April), 2002: pp 160-167
IMMUNO(BIO)THERAPY FOR LIVER METASTASES
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resistant tumors.13 The major drawback of this approach is significant systemic toxicity that may results in treatment-related death in some cases. For this reason, regional treatment with BRM has been investigated in an effort to increase the effectiveness of treatment for liver metastases and to minimize systemic toxicity (Table 1). Although the number of patients in each clinical study is small, there is an obvious trend favoring locoregional chemoimmunotherapy over chemotherapy alone. Hepatic arterial infusion (HAI) of BRM has been combined with chemotherapy. Despite the immunosuppressive character of chemotherapeutic drugs, their combination with cytokines has been reported to be agonistic in treating secondary liver tumors. It has been reported that chemotherapeutic drugs could augment immune responses depending on dosage and timing of administra-
tion.19 The administration of BRM can change the metabolism of chemotherapy drugs by augmenting hepatic extraction.20 It is also reported that combined therapy induces expression of the Fas receptor on the surface of tumor cells and make the tumor cells susceptible to apoptosis induced by Fas-Fas ligand interaction.21 Historically, Patt et al treated 30 patients with liver tumors with HAI of Corynebacterium parvum combined with chemotherapy.22 The treated liver tumors included metastases from 16 colon cancers and five breast cancers, as well as two primary hepatocellular carcinomas. The tumors were confined to the liver in 28 patients. The combined chemotherapy regimens were selected based on the primary tumors. In 18 evaluable patients with liver metastases, there were four partial responses (PRs), six minimum responses (MRs), and four patients had stable disease (SD). Six deaths were
Table 1. Regional Liver Treatment With BRM
Investigators
Primary Site of Liver Metastasis
Lygidakis et al,1 1996
Colorectal cancer
Okuno et al,2 1999 Boura et al,14 1999
Colorectal cancer
Okuno et al,15 1996
Colorectal cancer
Lygidakis et al,16 1995
Colorectal cancer
Libutti et al,4 2000 Bartlett et al,17 2001 Alexander et al,18 2000
Pancreatic cancer
Drugs
Route
No. of Evaluable Patients
IL-2, IFN-␥/MMC, Hepatic artery, 33 5-FU, splenic leucovorin artery IL-2/MMC, 5-FU Hepatic artery 25 IL-2, IFN-␥/MMC, Hepatic artery, 17 carboplatin, splenic mitoxantrone artery, superior mesenteric artery IL-2/MMC, 5-FU Hepatic artery 18
IL-2, IFN-␥/MMC, Hepatic artery, 5-FU, splenic leucovorin, artery carboplatin, epirubicin Colorectal cancer/ TNF␣/melphalan Hepatic artery uveal melanoma/ (IHP) others Colorectal cancer TNF␣/melphalan Hepatic artery (IHP) Uveal melanoma TNF␣/melphalan Hepatic artery (IHP)
19
Response 7 CR, 14 PR, 3 SD
6 CR, 13 PR
Remarks Survival benefit over intrahepatic chemotherapy Superior to intrahepatic or systemic chemotherapy
7 PR, 8 SD
Adjuvant; 4 recurrences Survival benefit over surgery without liver ⫹ intrahepatic involvement chemotherapy or surgery alone Adjuvant; Survival benefit over surgery no recurrence alone
48
1 CR, 35 PR
31
24 PR
11
2 CR, 6 PR
Grade 3 or greater liver toxicity; 76%
Abbreviations: BRM, biological response modifiers; IFN-␥, interferon gamma; MMC, mitomycin C; 5-FU, 5-fluorouracil; TNF␣, tumor necrosis factor alpha; IHP, isolated liver perfusion; CR, complete response; PR, partial response; SD, stable disease.
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reported within 5 to 14 days after beginning the treatment, four of which were tumor-related and two of which were related to drug toxicity. More recently, Lygidakis et al1 conducted a prospective randomized trial with HAI in patients with advanced metastatic liver disease from colorectal cancer. Forty-eight patients were randomly assigned to either regional treatment with mitomycin C (MMC), 5-fluorouracil (5-FU), and leucovorin, or chemoimmunotherapy with IL-2 and IFN-␥ combined with the above regimen. All medications were emulsified in an ethiodized oil (Lipiodol, Guerbet) and diatrizoate (Urografin, Schering) mixture. For the first 5 days of immunotherapy, treatments were given via the splenic artery, followed by a 5-day course of the same regimen via the hepatic artery. The chemotherapy was given via the hepatic artery. There were seven complete responses (CRs), 14 PRs, and three SD among 33 patients treated with chemoimmunotherapy. In contrast, only two patients achieved PR among 15 treated with intrahepatic chemotherapy. The median survival of patients treated with chemoimmunotherapy was 20.3 months and was significantly longer than that of patients treated with intrahepatic chemotherapy (9.9 months). Regional chemoimmunotherapies have also been tested on an adjuvant basis.15,16 Okuno et al treated 18 patients with liver metastasis from colorectal cancer using intrahepatic chemoimmunotherapy.15 Patients were treated with intrahepatic arterial infusion with IL-2, MMC, and 5-FU after complete resection of hepatic metastasis. Fourteen of 18 patients were alive and disease-free with a median postoperative follow-up of 28.5 months. Recurrence developed in four of 18 patients. Among these four patients, three developed metastases in the lung and one developed a metastasis in the pelvis. There was no recurrence in the liver. Lygidakis et al conducted a randomized clinical trial with chemoimmunotherapy for liver metastases from colorectal cancer.16 Forty patients with liver metastases were randomized to either surgery alone (group A; n ⫽ 20) or surgery plus postoperative chemoimmunotherapy (group B; n ⫽ 20). For the patients in group B, catheters were introduced into the hepatic artery and also into the splenic artery after the resection of liver metastasis. Twenty days after the liver resection, a 10-day course of regional immunotherapy with IL-2 and IFN-␥ emulsified in Lipiodol and Urografin
TAKAMI SATO
was initiated. Fifteen days after the completion of regional immunotherapy, a bolus infusion of Lipiodol, Urografin, MMC, carboplatin, epirubicin, 5-FU, leucovorin, and IFN-␥ was administered via the hepatic artery. The treatment was repeated every 3 months for the first year, every 4 months for the second year, and then every 6 months for the third year. There was a significant difference between two groups (surgery alone v surgery plus chemoimmunotherapy) in terms of the percentage of surviving patients who were disease-free (55% v 100%, P ⬍ .001), the percentage of patients who developed intrahepatic recurrence (40% v 0%, P ⬍ .001), median survival (11 v 30 months, P ⬍ .001), and survival (16/20 v 19/20). Isolated hepatic perfusion (IHP) enables increases in dose and time of exposure of chemotherapy drugs or BRM to the liver tumor without significant systemic toxicity. Libutti et al conducted a clinical trial with IHP using TNF and melphalan for patients with unresectable liver tumors.4 Fifty patients including 37 with colorectal carcinoma and eight with uveal melanoma were treated with IHP in which 1.0 mg of TNF␣ and 1.5 mg/kg of melphalan were given for 1 hour at moderate hyperthermia. The overall response rate in 48 evaluable patients was 75% (CR 2%, PR 73%). There were two treatment-related deaths (4%) due to liver insufficiency. Bartlett et al reported the result of IHP for metastatic colorectal cancer.17 Thirty-two patients with unresectable hepatic metastases from colorectal carcinoma were treated with IHP using TNF␣ and melphalan and 24 (77%) radiographic responses (PR) were reported in 31 evaluable patients. A series of 22 patients with uveal melanoma metastatic to the liver was treated using IHP with melphalan alone (n ⫽ 11) or melpharan and TNF␣ (n ⫽ 11).18 Among the 11 patients who received melphalan and TNF␣, there were two CRs and four PRs for an overall response rate of 54.5%. Although IHP with melphalan produced a similar response rate (0 CR, 7 PR), the median duration of response in patients treated with melphalan and TNF␣ was longer than that of melphalan alone (14 months v 6 months). However, the addition of TNF␣ to melphalan is associated with significant regional and systemic toxicity including hypotension and hyperbilirubinemia. This is partly due to leak of TNF to systemic circulation and also due to induction of inflammatory cytokines such as IL-6
IMMUNO(BIO)THERAPY FOR LIVER METASTASES
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and IL-8.23 Since 1997, clinical grade TNF␣ is no longer available in the United States for IHP and no further clinical trials have been conducted. LOCOREGIONAL ADAPTIVE IMMUNOTHERAPY FOR LIVER METASTASIS
Adoptive cellular therapy with tumor-specific or nonspecific killer cells has been reported in several clinical trials.13,24,25 However, the role of ex vivo– activated killer cells is controversial. One possible reason that limits the efficacy of intravenously administered adaptive immunotherapy (AIT) is the poor accumulation of these killer cells in the tumor sites. To overcome this limitation, locoregional approaches have been investigated for metastatic liver tumors (Table 2). The results of this approach for metastatic tumors are rather disappointing. Keilholz et al reported that regional infusion of LAK cells via the hepatic artery or the
portal vein produced regression of liver tumors in three of nine cutaneous melanoma patients with liver metastasis.29 However, there was no response in five uveal melanoma patients. Hennemann et al infused the hepatic artery with activated macrophages for liver metastases from gastrointestinal malignancies including six colorectal carcinomas and one gastric cancer.31 There was no radiographic response and all patients progressed. To improve response of locoregional AIT, a Japanese group combined an immunostimulant, OK-432 (a preparation from Streptococcus pyogens A3) to AIT.3,32-34 Okino et al reported that nine of 14 patients with breast cancer metastatic to the liver responded to AIT combined with OK-432 infused through the hepatic artery.3 In contrast, none of five patients who received the treatment intravenously showed response. Direct injection of killer cells into tumor was also investigated to increase the number of effecter cells
Table 2. Locoregional AIT
Investigators al,26
Primary Site of Liver Metastasis
Treatment
Route of AIT
No. of Evaluable Patients
Response
Takayama et 1991 Matsuhashi et al,27 1990 Kobari et al,28 2000
Colorectal cancer Colorectal cancer Pancreatic cancer
TIL/IL-2/chemotherapy
Hepatic artery
2
1 PR
LAK/IL-2
Hepatic artery
3
3 PD
LAK/IL-2
Portal vein
12
3-yr survival 36%
Keilholz et al,29 1994
Melanoma
LAK/IL-2
9 skin, 5 eye
Skin; 2 CR, 1 PR; eye; 5 PD
Komatsu et al,30 1990
GI malignancy
LAK/IL-2
Portal vein or hepatic artery Hepatic artery
3 SD, 1 PD
Hennemann et al,31 1995 Satoh et al,32 1993
GI malignancy
Macrophages/IFN-␥
Hepatic artery
GI malignancy
OK 432/CTL/ chemotherapy
Hepatic artery or portal vein
2 stomach, 1 gall bladder, 1 colon 6 colorectal, 1 stomach 10 stomach, 8 colorectal
Okino et al,3 1990 Yamasaki et al,33 1992 Kan et al,34 1994 Ferlazzo et al,35 1997
Breast cancer
OK 432/CTL/ chemotherapy
Hepatic artery
26
Colon/breast/ kidney
LAK/IL-2
Direct injection
4 colon, 3 breast, 1 kidney
Remarks
Adjuvant treatment after surgery and radiation therapy
7 PD Stomach: 3 PR, 1 MR, 3 SD: Colorectal: 2 CR, 5 SD 6 CR, 11 PR, 5 SD
Median survival with CR ⫹ PR; 22.8 months
2 CR, 1 PR, 4 SD
Abbreviations: AIT, adaptive immunotherapy; GI, gastrointestinal; TIL, tumor-infiltrating lymphocytes; IL-2, interleukin-2; LAK, lymphokineactivated killer cells; IFN-␥, interferon gamma; CTL, cytotoxic T lymphocytes; MR, mixed response.
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in the tumor site. Ferlazzo et al directly deliver LAK cells and IL-2 into the liver tumors using the ultrasound technique.35 Eight patients with liver metastases were treated with this approach and two CRs, one PR, and four SD were reported. The major drawback of locoregional AIT is the complexity of the treatment. Preparation of LAK cells or TIL requires ex vivo expansion of cells, which is labor-intensive and time-consuming. Therefore, the number of patients who have been treated with this approach is limited and the interpretation of the results in each study is difficult.
TAKAMI SATO
IMMUNOEMBOLIZATION OF LIVER METASTASES
Chemoembolization has been used for hepatocellular carcinoma36 and several other types of tumors metastatic to the liver including melanoma,37 carcinoid,38 colon cancer,39 and leiomyosarcoma.40 The major problem in the treatment of metastatic liver tumors with this approach is subsequent development of extrahepatic metastasis.12 Patel et al reported that two thirds of patients with metastatic uveal melanoma in the liver subsequently developed extrahepatic metastasis after
Fig 1. Regression of liver metastases after immunoembolization with GM-CSF. A patient with multiple liver metastases and subcutaneous metastases from uveal melanoma was treated by immunoembolization of the hepatic artery with 500 g of GM-CSF emulsified in ethiodized oil, followed by gelatin sponge pledgets. After the first cycle, the follow-up computed tomography (CT) scan of the abdomen revealed significant shrinkage of multiple liver metastases with accumulation of ethiodized oil in the tumors. (A) CT scan prior to treatment; (B) after the first cycle of immunoeoblization.
IMMUNO(BIO)THERAPY FOR LIVER METASTASES
successful treatment of their liver metastases with chemoembolization.12 Immunoembolization of the liver tumor is designed to overcome this limitation. The rationales for this approach include (1) embolization of the hepatic artery provides a major ischemic attack on liver tumors; (2) regional infusion of immunostimulants induces an inflammatory response in the tumor and the surrounding tissues, which elim-
Fig 2. Inflammatory response developed in a subcutaneous metastasis after immunoembolization of the liver metastases with GM-CSF. A subcutaneous metastasis was removed from the same patient as in Fig 1 after immunoembolization of the liver metastases. The subcutaneous tumor was significantly infiltrated with mononuclear cells, which was accompanied with a hemorrhagic change. Immunohistochemical staining revealed that infiltrating mononuclear cells are CD3ⴙ lymphocytes, of which approximately 40% to 50% were positive for CD8. (Top) Hematoxylin & eosin staining; ⴛ 100. (Bottom) Immunohistochemical staining with CD8; original magnification ⴛ 200.
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inates residual tumor cells; and (3) local stimulation of the immune system may result in development of a systemic immune response against tumor cells, which suppresses the growth of extrahepatic metastases. This concept was originally applied to hepatocellular carcinoma. Kanai et al reported the first clinical trial with transarterial immunoembolization (TIE) of hepatocellular carcinoma with a mixture of OK-432 and fibrinogen.41 OK-432 was
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TAKAMI SATO
mixed with fibrinogen, thrombin, and Lipiodol and infused into the hepatic artery. They initially treated 19 patients with advanced hepatocellular carcinoma who failed to respond to conventional therapies. A marked reduction in tumor size was observed in six patients. A second series of six patients who did not receive any previous treatment were treated with the same technique. These patients subsequently underwent hepatic resection at 6 to 48 days following TIE. Microscopic examination of embolized hepatocellular carcinoma revealed massive infiltration of mononuclear cells around tumor cell nests. Lytic necrosis as well as coagulation necrosis of the main tumor and intrahepatic metastasis were documented. Our group recently developed a new immunoembolization approach using granulocyte-macrophage colony-stimulating factor (GM-CSF).42,43 GM-CSF (Leukine, Immunex Corp, Seattle, WA) was used to stimulate antigen-presenting cells in the liver metastases. Thirteen patients with metastatic melanoma in the liver (12 uveal melanoma, one skin melanoma) were treated with this technique in a phase I clinical study. They were treated with varying doses of GM-CSF (25 g to 1,000 g) emulsified in ethiodized oil. The responses were one CR, four PRs, and five SD among 12 evaluable patients (Fig 1). Extrahepatic metastases were removed in five patients after the immunoembolization of the liver metastases. Among these patients, two developed a significant immune response in the remote metastases (Fig 2). Based on this promising result, a phase II clinical trial is being designed. INTRALESIONAL GENE THERAPY TO ENHANCE AN IMMUNE RESPONSE
Direct delivery of a gene that stimulates the immune system has been tried.44 Rubin et al reported the result of the phase I study with direct gene transfer of an allogeneic histocompatibility antigen, HAL-B7.44 Under ultrasound guidance, liver metastases from colorectal carcinoma were injected with a plasmid vector containing genes of HLA-B7 and 2-microglobulin. Among 15 evaluable patients, plasmid DNA was detected in 14 patients and there was no adverse event directly related to the study drug. However, there was no objective regression of injected or uninjected liver metastases. Five of 15 patients had SD for more than 100 days.
CONCLUSION
Locoregional immuno(bio)therapy is a reasonable approach for metastatic liver tumors that are otherwise resistant to standard treatments such as chemotherapy. This approach can result in local control of the disease as well as establishment of systemic immune response to tumor cells. However, the number of patients in the past studies is small and treatment modalities were too variable to develop a sound consensus on this approach. In the future, clinical trials must be of a larger scale to adequately define the efficacy of locoregional immunotherapy for metastatic tumors in the liver. REFERENCES 1. Lygidakis NJ, Stringaris K, Kokinis K, et al: Locoregional chemotherapy versus locoregional combined immuno-chemotherapy for patients with advanced metastatic liver disease of colorectal origin: A prospective randomized study. Hepatogastroenterology 43:212-220, 1996 2. Okuno K, Kaneda K, Yasutomi M: Regional IL-2-based immunochemotherapy of colorectal liver metastases. Hepatogastroenterology 46:1263-1267, 1999 3. Okino T, Kan N, Nakanishi M, et al: The therapeutic effect of OK-432-combined adoptive immunotherapy against liver metastases from breast cancer. J Cancer Res Clin Oncol 116:197-202, 1990 4. Libutti SK, Bartlett DL, Fraker DL, et al: Technique and results of hyperthermic isolated hepatic perfusion with tumor necrosis factor and melphalan for the treatment of unresectable hepatic malignancies. J Am Coll Surg 191:519-530, 2000 5. Malter M, Friedrich E, Suss R: Liver as a tumor cell killing organ: Kupffer cells and natural killers. Cancer Res 46:30553060, 1986 6. Seki S, Abo T, Masuda T, et al: Identification of activated T cell receptor ␥␦ lymphocytes in the liver of tumor-bearing hosts. J Clin Invest 86:409-416, 1990 7. Bouwens L, Marinelli A, Kuppen PJ, et al: Electron microscopic observations on the accumulation of large granular lymphocytes (pit cells) and Kupffer cells in the liver of rats treated with continuous infusion of interleukin-2. Hepatology 12:1365-1370, 1990 8. Bouwens L, Jacobs R, Remels L, et al: Natural cytotoxicity of rat hepatic natural killer cells and macrophages against a syngeneic colon adenocarcinoma. Cancer Immunol Immunother 27:137-141, 1988 9. Gennari L: Liver metastases: A many-sided therapeutical problem. Hepatogastroenterology 39:5-9, 1992 10. Hohenberger P, Schlag P, Schwarz V, et al: Tumor recurrence and options for further treatment after resection of liver metastases in patients with colorectal cancer. J Surg Oncol 44:245-251, 1990 11. Bozetti F, Bignami P, Morabito A, et al: Patterns of failure following surgical resection of colorectal cancer liver metastases. Ann Surg 205:264-269, 1987 12. Patel K, Sullivan K, Aoyama T, et al: Hepatic artery chemoembolization (HAC) with BCNU for treatment of metastatic uveal melanoma. Proc Am Soc Clin Oncol 20:356, 2001 (abstr)
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13. Rosenberg SA, Lotze MT, Muul LM, et al: A progress report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cells and interleukin-2 or high-dose interleukin-2 alone. N Engl J Med 316:889-987, 1987 14. Boura P, Kountouras J, Lygidakis NJ, et al: Transplenic and transtumoral in vivo immunostimulation: Effect on cellular immunity parameters. Hepatogastroenterology 46:799-803, 1999 15. Okuno K, Shigeoka H, Lee Y-S, et al: Adjuvant hepatic arterial IL-2 and MMC, 5-FU after curative resection of colorectal liver metastases. Hepatogastroenterology 43:688-691, 1996 16. Lygidakis NJ, Ziras N, Parissis J: Resection versus resection combined with adjuvant pre- and post-operative chemotherapy-immunotherapy for metastatic colorectal liver cancer. A new look at an old problem. Hepatogastroenterology 42:155161, 1995 17. Bartlett DL, Libutti SK, Figg WD, et al: Isolated hepatic perfusion for unresectable hepatic metastases from colorectal cancer. Surgery 129:176-187, 2001 18. Alexander HR, Libutti SK, Bartlett DL, et al: A phase I-II study of isolated hepatic perfusion using melphalan with or without tumor necrosis factor for patients with ocular melanoma metastatic to liver. Clin Cancer Res 6:3062-3070, 2000 19. Maguire HC Jr, Ettore VL: Enhancement of dinitrochlorobenzene (DNCB) contact sensitization by cyclophosphamide in the guinea pig. J Invest Dermatol 48:39-42, 1967 20. Okuno K, Kobayashi S, Jinnai H, et al: IL-2 perfusion to the liver augments the hepatic extraction rate of accompanying anticancer drugs. Surg Today 26:662-664, 1996 21. Micheau O, Solary E, Hammann A, et al: Sensitization of cancer cells treated with cytotoxic drugs to Fas-mediated cytotoxicity. J Natl Cancer Inst 89:783-789, 1997 22. Patt YZ, Wallace S, Hersh EM, et al: Hepatic arterial infusion of Corynebacterium parvum and chemotherapy. Surg Gynecol Obstet 147:897-902, 1978 23. Lans TE, Bartlett DL, Libutti SK, et al: Role of tumor necrosis factor on toxicity and cytokine production after isolated hepatic perfusion. Clin Cancer Res 7:784-790, 2001. 24. Mazumder A, Eberlein TJ, Grimm EA et al: Phase I study of the adoptive immunotherapy of human cancer with lectin activated autologous mononuclear cells. Cancer 53:896905, 1984 25. Kradin RL, Kurnick JT, Lazarus DS, et al: Tumor-infiltrating lymphocytes and interleukin-2 in treatment of advanced cancer. Lancet 1:577-580, 1989 26. Takayama T, Makuuchi M, Sekine T, et al: Distribution and therapeutic effect of intraarterially transferred tumor-infiltrating lymphocytes in hepatic malignancies. A preliminary report. Cancer 68:2391-2396, 1991 27. Matsuhashi N, Moriyama T, Nakamura I, et al: Adoptive immunotherapy of primary and metastatic liver cancer via hepatic artery catheter. Eur J Cancer 26:1106-1107, 1990 28. Kobari M, Egawa S, Shibuya K, et al: Effect of intraportal adoptive immunotherapy on liver metastases after resection of pancreatic cancer. Br J Surg 87:43-48, 2000 29. Keiholz U, Scheibenbogen C, Brado M, et al: Regional adoptive immunotherapy with interleukin-2 and lymphokineactivated killer (LAK) cells for liver metastases. Eur J Cancer 30A:103-105, 1994
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30. Komatsu T, Yamauchi K, Furukawa T, et al: Transcatheter arterial injection of autologous lymphokine-activated killer (LAK) cells into patients with liver cancers. J Clin Immunol 10:167-174, 1990 31. Hennemann B, Scheibenbogen C, Schumichen C, et al: Intrahepatic adoptive immunotherapy with autologous tumorcytotoxic macrophages in patients with cancer. J Immunother 18:19-27, 1995 32. Satoh K, Kan N, Okino T, et al: The therapeutic effect of OK-432-combined adoptive immunotherapy against liver metastases from gastric and colorectal cancers. Biotherapy 6:41-49, 1993 33. Yamasaki S, Okino T, Kan N, et al: Factors influencing the response and survival of patients with liver metastases from breast cancer receiving OK-432-combined adoptive immunotherapy. J Cancer Res Clin Oncol 118:157-162, 1992 34. Kan N, Yamasaki S, Kodama H, et al: Bone metastasis as a prognostic factor in breast cancer patients with liver metastasis given OK-432-combined adoptive immunotherapy via the hepatic artery. Biotherapy 6:245-250, 1994 35. Ferlazzo G, Scisca C, Iemmo R, et al: Intralesional sonographically guided injections of lymphokine-activated killer cells and recombinant interleukin-2 for the treatment of liver tumors: A pilot study. J Immunother 20:158-163, 1997 36. Kasugai H, Kojima J, Tatsuta M, et al: Treatment of hepatocellular carcinoma by transcatheter arterial embolization combined with intraarterial infusion of a mixture of cisplatin and ethiodized oil. Gasteroenterology 97:965-971, 1989 37. Mavligit GM, Charnsangavej C, Carrasco H, et al: Regression of ocular melanoma metastatic to the liver after hepatic arterial chemoembolization with cisplatin and polyvinyl sponge. JAMA 260:947-976, 1988 38. Carrasco CH, Charnsangavej C, Ajani J, et al: The carcinoid syndrome: Palliation by hepatic artery embolization. AJR 147:149-154, 1986 39. Daniels J, Pentecost M, Teitelbaum G, et al: Hepatic artery chemoembolization (HAE) for carcinoma of colon using angiostat collagen and cis-platin, mitomycin, and doxorubicin: response, survival, and serum drug levels. Proc Am Soc Clin Oncol 11:171, 1992 (abstr) 40. Mavligit GM, Zukwiski AA, Ellis LM, et al: Gastrointestinal leiomyosarcoma metastatic to the liver. Cancer 75: 2083-2088, 1995 41. Kannai T, Monden M, Sakon M, et al: New development of transarterial immunoembolization (TIE) for therapy of hepatocellular carcinoma with intrahepatic metastases. Cancer Chemother Pharmacol 33:S48-S54, 1994 (suppl) 42. Sato T, Terai M, Huandong Y, et al: Systemic immune response after immunoembolization of liver metastasis with granulocyte-macrophage colony stimulating factor (GM-CSF). Proc Am Assoc Cancer Res (in press) 43. Aoyama T, Sullivan K, Terai M, et al: Immunoembolization of malignant liver tumors with granulocyte macrophage colony stimulating factor (GM-CSF) and ethiodized oil followed by gelatin sponge pledgets. Proc Am Soc Clin Oncol (in press) 44. Rubin J, Galanis E, Pitot HC, et al: Phase I study of immunotherapy of hepatic metastases of colorectal carcinoma by direct gene transfer of an allogeneic histocompatibility antigen, HLA-B7. Gene Ther 4:419-425, 1997
L
OCOREGIONAL immuno(bio)therapy for liver metastases offers several advantages over systemic immuno(bio)therapy: (1) direct administration of immune cells or immunostimulants into the tumor alters the environment within the tumor and may break immunotolerance elicited by tumor cells; (2) local administration of cytokines, such as interleukin-2 (IL-2), interferons (IFNs), or tumor necrosis factor alpha (TNF-␣), minimizes systemic toxicity; and (3) destruction of tumor cells in situ provides tumor antigens to the host immune system, which may result in a systemic immune response against tumor cells (in situ can-
From the Division of Medical Oncology, Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA. Address reprint requests to Takami Sato, MD, Division of Medical Oncology, Jefferson Medical College of Thomas Jefferson University, 1025 Walnut St, Suite 312, Philadelphia, PA 19107. Copyright 2002, Elsevier Science (USA). All rights reserved. 0093-7754/02/2902-0012$35.00/0 doi:10.1053/sonc.2002.31716 160
cer vaccine). Various locoregional immunological approaches have been developed, including intrahepatic infusion of cytokines combined with chemotherapy, adoptive immunotherapy with activated lymphocytes, or embolization of liver tumors with immunostimulants. Although the number of patients in each study is small and treatment modalities are variable, bonafide responses have been reported.1-4 These approaches would be especially useful in local control of unresectable, chemotherapy-resistant liver metastasis from melanoma, gastrointestinal malignancies, or breast cancer. RATIONALE FOR IMMUNO(BIO)THERAPY FOR LIVER METASTASES
One of the critical questions regarding local immunotherapy for liver metastasis is whether immunological responses can be induced in the liver. In this regard, the liver is the largest organ of the reticuloendothelial system and would be the appropriate target for immunotherapy. The liver contains more than 70% of all tissue macrophages (Kupffer cells) and eliminates bacteria and foreign bodies from the circulation. The liver responds rapidly to inflammation, as a secondary response to proinflammatory cytokines including IL-1, TNF-␣, and IL-6. In addition, hepatic sinusoidal lymphocytes (HSL), originally referred to as pit cells, have functions of natural killer (NK) cells.5 NK T cells and CD3⫹ ␥␦ T cells are also present in the liver.6 It has been reported that these immune cells in the liver can be activated by various cytokines including IL-2 and IFN-␥ and demonstrate antitumor activities.7,8 Since only 20% of patients with metastasis would be candidates for complete surgical resection9 and the majority of these patients will subsequently develop a local or systemic recurrence after local treatments of liver metastases,10-12 a new treatment modality to control local disease and to prevent systemic progression is needed. In this respect, locoregional immuno(bio)therapy is an attractive and reasonable approach for the management of liver metastasis. REGIONAL TREATMENT WITH BIOLOGICAL RESPONSE MODIFIERS
Systemic administration of biological response modifiers (BRM) produces durable responses in limited number of patients with chemotherapySeminars in Oncology, Vol 29, No 2 (April), 2002: pp 160-167
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resistant tumors.13 The major drawback of this approach is significant systemic toxicity that may results in treatment-related death in some cases. For this reason, regional treatment with BRM has been investigated in an effort to increase the effectiveness of treatment for liver metastases and to minimize systemic toxicity (Table 1). Although the number of patients in each clinical study is small, there is an obvious trend favoring locoregional chemoimmunotherapy over chemotherapy alone. Hepatic arterial infusion (HAI) of BRM has been combined with chemotherapy. Despite the immunosuppressive character of chemotherapeutic drugs, their combination with cytokines has been reported to be agonistic in treating secondary liver tumors. It has been reported that chemotherapeutic drugs could augment immune responses depending on dosage and timing of administra-
tion.19 The administration of BRM can change the metabolism of chemotherapy drugs by augmenting hepatic extraction.20 It is also reported that combined therapy induces expression of the Fas receptor on the surface of tumor cells and make the tumor cells susceptible to apoptosis induced by Fas-Fas ligand interaction.21 Historically, Patt et al treated 30 patients with liver tumors with HAI of Corynebacterium parvum combined with chemotherapy.22 The treated liver tumors included metastases from 16 colon cancers and five breast cancers, as well as two primary hepatocellular carcinomas. The tumors were confined to the liver in 28 patients. The combined chemotherapy regimens were selected based on the primary tumors. In 18 evaluable patients with liver metastases, there were four partial responses (PRs), six minimum responses (MRs), and four patients had stable disease (SD). Six deaths were
Table 1. Regional Liver Treatment With BRM
Investigators
Primary Site of Liver Metastasis
Lygidakis et al,1 1996
Colorectal cancer
Okuno et al,2 1999 Boura et al,14 1999
Colorectal cancer
Okuno et al,15 1996
Colorectal cancer
Lygidakis et al,16 1995
Colorectal cancer
Libutti et al,4 2000 Bartlett et al,17 2001 Alexander et al,18 2000
Pancreatic cancer
Drugs
Route
No. of Evaluable Patients
IL-2, IFN-␥/MMC, Hepatic artery, 33 5-FU, splenic leucovorin artery IL-2/MMC, 5-FU Hepatic artery 25 IL-2, IFN-␥/MMC, Hepatic artery, 17 carboplatin, splenic mitoxantrone artery, superior mesenteric artery IL-2/MMC, 5-FU Hepatic artery 18
IL-2, IFN-␥/MMC, Hepatic artery, 5-FU, splenic leucovorin, artery carboplatin, epirubicin Colorectal cancer/ TNF␣/melphalan Hepatic artery uveal melanoma/ (IHP) others Colorectal cancer TNF␣/melphalan Hepatic artery (IHP) Uveal melanoma TNF␣/melphalan Hepatic artery (IHP)
19
Response 7 CR, 14 PR, 3 SD
6 CR, 13 PR
Remarks Survival benefit over intrahepatic chemotherapy Superior to intrahepatic or systemic chemotherapy
7 PR, 8 SD
Adjuvant; 4 recurrences Survival benefit over surgery without liver ⫹ intrahepatic involvement chemotherapy or surgery alone Adjuvant; Survival benefit over surgery no recurrence alone
48
1 CR, 35 PR
31
24 PR
11
2 CR, 6 PR
Grade 3 or greater liver toxicity; 76%
Abbreviations: BRM, biological response modifiers; IFN-␥, interferon gamma; MMC, mitomycin C; 5-FU, 5-fluorouracil; TNF␣, tumor necrosis factor alpha; IHP, isolated liver perfusion; CR, complete response; PR, partial response; SD, stable disease.
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reported within 5 to 14 days after beginning the treatment, four of which were tumor-related and two of which were related to drug toxicity. More recently, Lygidakis et al1 conducted a prospective randomized trial with HAI in patients with advanced metastatic liver disease from colorectal cancer. Forty-eight patients were randomly assigned to either regional treatment with mitomycin C (MMC), 5-fluorouracil (5-FU), and leucovorin, or chemoimmunotherapy with IL-2 and IFN-␥ combined with the above regimen. All medications were emulsified in an ethiodized oil (Lipiodol, Guerbet) and diatrizoate (Urografin, Schering) mixture. For the first 5 days of immunotherapy, treatments were given via the splenic artery, followed by a 5-day course of the same regimen via the hepatic artery. The chemotherapy was given via the hepatic artery. There were seven complete responses (CRs), 14 PRs, and three SD among 33 patients treated with chemoimmunotherapy. In contrast, only two patients achieved PR among 15 treated with intrahepatic chemotherapy. The median survival of patients treated with chemoimmunotherapy was 20.3 months and was significantly longer than that of patients treated with intrahepatic chemotherapy (9.9 months). Regional chemoimmunotherapies have also been tested on an adjuvant basis.15,16 Okuno et al treated 18 patients with liver metastasis from colorectal cancer using intrahepatic chemoimmunotherapy.15 Patients were treated with intrahepatic arterial infusion with IL-2, MMC, and 5-FU after complete resection of hepatic metastasis. Fourteen of 18 patients were alive and disease-free with a median postoperative follow-up of 28.5 months. Recurrence developed in four of 18 patients. Among these four patients, three developed metastases in the lung and one developed a metastasis in the pelvis. There was no recurrence in the liver. Lygidakis et al conducted a randomized clinical trial with chemoimmunotherapy for liver metastases from colorectal cancer.16 Forty patients with liver metastases were randomized to either surgery alone (group A; n ⫽ 20) or surgery plus postoperative chemoimmunotherapy (group B; n ⫽ 20). For the patients in group B, catheters were introduced into the hepatic artery and also into the splenic artery after the resection of liver metastasis. Twenty days after the liver resection, a 10-day course of regional immunotherapy with IL-2 and IFN-␥ emulsified in Lipiodol and Urografin
TAKAMI SATO
was initiated. Fifteen days after the completion of regional immunotherapy, a bolus infusion of Lipiodol, Urografin, MMC, carboplatin, epirubicin, 5-FU, leucovorin, and IFN-␥ was administered via the hepatic artery. The treatment was repeated every 3 months for the first year, every 4 months for the second year, and then every 6 months for the third year. There was a significant difference between two groups (surgery alone v surgery plus chemoimmunotherapy) in terms of the percentage of surviving patients who were disease-free (55% v 100%, P ⬍ .001), the percentage of patients who developed intrahepatic recurrence (40% v 0%, P ⬍ .001), median survival (11 v 30 months, P ⬍ .001), and survival (16/20 v 19/20). Isolated hepatic perfusion (IHP) enables increases in dose and time of exposure of chemotherapy drugs or BRM to the liver tumor without significant systemic toxicity. Libutti et al conducted a clinical trial with IHP using TNF and melphalan for patients with unresectable liver tumors.4 Fifty patients including 37 with colorectal carcinoma and eight with uveal melanoma were treated with IHP in which 1.0 mg of TNF␣ and 1.5 mg/kg of melphalan were given for 1 hour at moderate hyperthermia. The overall response rate in 48 evaluable patients was 75% (CR 2%, PR 73%). There were two treatment-related deaths (4%) due to liver insufficiency. Bartlett et al reported the result of IHP for metastatic colorectal cancer.17 Thirty-two patients with unresectable hepatic metastases from colorectal carcinoma were treated with IHP using TNF␣ and melphalan and 24 (77%) radiographic responses (PR) were reported in 31 evaluable patients. A series of 22 patients with uveal melanoma metastatic to the liver was treated using IHP with melphalan alone (n ⫽ 11) or melpharan and TNF␣ (n ⫽ 11).18 Among the 11 patients who received melphalan and TNF␣, there were two CRs and four PRs for an overall response rate of 54.5%. Although IHP with melphalan produced a similar response rate (0 CR, 7 PR), the median duration of response in patients treated with melphalan and TNF␣ was longer than that of melphalan alone (14 months v 6 months). However, the addition of TNF␣ to melphalan is associated with significant regional and systemic toxicity including hypotension and hyperbilirubinemia. This is partly due to leak of TNF to systemic circulation and also due to induction of inflammatory cytokines such as IL-6
IMMUNO(BIO)THERAPY FOR LIVER METASTASES
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and IL-8.23 Since 1997, clinical grade TNF␣ is no longer available in the United States for IHP and no further clinical trials have been conducted. LOCOREGIONAL ADAPTIVE IMMUNOTHERAPY FOR LIVER METASTASIS
Adoptive cellular therapy with tumor-specific or nonspecific killer cells has been reported in several clinical trials.13,24,25 However, the role of ex vivo– activated killer cells is controversial. One possible reason that limits the efficacy of intravenously administered adaptive immunotherapy (AIT) is the poor accumulation of these killer cells in the tumor sites. To overcome this limitation, locoregional approaches have been investigated for metastatic liver tumors (Table 2). The results of this approach for metastatic tumors are rather disappointing. Keilholz et al reported that regional infusion of LAK cells via the hepatic artery or the
portal vein produced regression of liver tumors in three of nine cutaneous melanoma patients with liver metastasis.29 However, there was no response in five uveal melanoma patients. Hennemann et al infused the hepatic artery with activated macrophages for liver metastases from gastrointestinal malignancies including six colorectal carcinomas and one gastric cancer.31 There was no radiographic response and all patients progressed. To improve response of locoregional AIT, a Japanese group combined an immunostimulant, OK-432 (a preparation from Streptococcus pyogens A3) to AIT.3,32-34 Okino et al reported that nine of 14 patients with breast cancer metastatic to the liver responded to AIT combined with OK-432 infused through the hepatic artery.3 In contrast, none of five patients who received the treatment intravenously showed response. Direct injection of killer cells into tumor was also investigated to increase the number of effecter cells
Table 2. Locoregional AIT
Investigators al,26
Primary Site of Liver Metastasis
Treatment
Route of AIT
No. of Evaluable Patients
Response
Takayama et 1991 Matsuhashi et al,27 1990 Kobari et al,28 2000
Colorectal cancer Colorectal cancer Pancreatic cancer
TIL/IL-2/chemotherapy
Hepatic artery
2
1 PR
LAK/IL-2
Hepatic artery
3
3 PD
LAK/IL-2
Portal vein
12
3-yr survival 36%
Keilholz et al,29 1994
Melanoma
LAK/IL-2
9 skin, 5 eye
Skin; 2 CR, 1 PR; eye; 5 PD
Komatsu et al,30 1990
GI malignancy
LAK/IL-2
Portal vein or hepatic artery Hepatic artery
3 SD, 1 PD
Hennemann et al,31 1995 Satoh et al,32 1993
GI malignancy
Macrophages/IFN-␥
Hepatic artery
GI malignancy
OK 432/CTL/ chemotherapy
Hepatic artery or portal vein
2 stomach, 1 gall bladder, 1 colon 6 colorectal, 1 stomach 10 stomach, 8 colorectal
Okino et al,3 1990 Yamasaki et al,33 1992 Kan et al,34 1994 Ferlazzo et al,35 1997
Breast cancer
OK 432/CTL/ chemotherapy
Hepatic artery
26
Colon/breast/ kidney
LAK/IL-2
Direct injection
4 colon, 3 breast, 1 kidney
Remarks
Adjuvant treatment after surgery and radiation therapy
7 PD Stomach: 3 PR, 1 MR, 3 SD: Colorectal: 2 CR, 5 SD 6 CR, 11 PR, 5 SD
Median survival with CR ⫹ PR; 22.8 months
2 CR, 1 PR, 4 SD
Abbreviations: AIT, adaptive immunotherapy; GI, gastrointestinal; TIL, tumor-infiltrating lymphocytes; IL-2, interleukin-2; LAK, lymphokineactivated killer cells; IFN-␥, interferon gamma; CTL, cytotoxic T lymphocytes; MR, mixed response.
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in the tumor site. Ferlazzo et al directly deliver LAK cells and IL-2 into the liver tumors using the ultrasound technique.35 Eight patients with liver metastases were treated with this approach and two CRs, one PR, and four SD were reported. The major drawback of locoregional AIT is the complexity of the treatment. Preparation of LAK cells or TIL requires ex vivo expansion of cells, which is labor-intensive and time-consuming. Therefore, the number of patients who have been treated with this approach is limited and the interpretation of the results in each study is difficult.
TAKAMI SATO
IMMUNOEMBOLIZATION OF LIVER METASTASES
Chemoembolization has been used for hepatocellular carcinoma36 and several other types of tumors metastatic to the liver including melanoma,37 carcinoid,38 colon cancer,39 and leiomyosarcoma.40 The major problem in the treatment of metastatic liver tumors with this approach is subsequent development of extrahepatic metastasis.12 Patel et al reported that two thirds of patients with metastatic uveal melanoma in the liver subsequently developed extrahepatic metastasis after
Fig 1. Regression of liver metastases after immunoembolization with GM-CSF. A patient with multiple liver metastases and subcutaneous metastases from uveal melanoma was treated by immunoembolization of the hepatic artery with 500 g of GM-CSF emulsified in ethiodized oil, followed by gelatin sponge pledgets. After the first cycle, the follow-up computed tomography (CT) scan of the abdomen revealed significant shrinkage of multiple liver metastases with accumulation of ethiodized oil in the tumors. (A) CT scan prior to treatment; (B) after the first cycle of immunoeoblization.
IMMUNO(BIO)THERAPY FOR LIVER METASTASES
successful treatment of their liver metastases with chemoembolization.12 Immunoembolization of the liver tumor is designed to overcome this limitation. The rationales for this approach include (1) embolization of the hepatic artery provides a major ischemic attack on liver tumors; (2) regional infusion of immunostimulants induces an inflammatory response in the tumor and the surrounding tissues, which elim-
Fig 2. Inflammatory response developed in a subcutaneous metastasis after immunoembolization of the liver metastases with GM-CSF. A subcutaneous metastasis was removed from the same patient as in Fig 1 after immunoembolization of the liver metastases. The subcutaneous tumor was significantly infiltrated with mononuclear cells, which was accompanied with a hemorrhagic change. Immunohistochemical staining revealed that infiltrating mononuclear cells are CD3ⴙ lymphocytes, of which approximately 40% to 50% were positive for CD8. (Top) Hematoxylin & eosin staining; ⴛ 100. (Bottom) Immunohistochemical staining with CD8; original magnification ⴛ 200.
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inates residual tumor cells; and (3) local stimulation of the immune system may result in development of a systemic immune response against tumor cells, which suppresses the growth of extrahepatic metastases. This concept was originally applied to hepatocellular carcinoma. Kanai et al reported the first clinical trial with transarterial immunoembolization (TIE) of hepatocellular carcinoma with a mixture of OK-432 and fibrinogen.41 OK-432 was
166
TAKAMI SATO
mixed with fibrinogen, thrombin, and Lipiodol and infused into the hepatic artery. They initially treated 19 patients with advanced hepatocellular carcinoma who failed to respond to conventional therapies. A marked reduction in tumor size was observed in six patients. A second series of six patients who did not receive any previous treatment were treated with the same technique. These patients subsequently underwent hepatic resection at 6 to 48 days following TIE. Microscopic examination of embolized hepatocellular carcinoma revealed massive infiltration of mononuclear cells around tumor cell nests. Lytic necrosis as well as coagulation necrosis of the main tumor and intrahepatic metastasis were documented. Our group recently developed a new immunoembolization approach using granulocyte-macrophage colony-stimulating factor (GM-CSF).42,43 GM-CSF (Leukine, Immunex Corp, Seattle, WA) was used to stimulate antigen-presenting cells in the liver metastases. Thirteen patients with metastatic melanoma in the liver (12 uveal melanoma, one skin melanoma) were treated with this technique in a phase I clinical study. They were treated with varying doses of GM-CSF (25 g to 1,000 g) emulsified in ethiodized oil. The responses were one CR, four PRs, and five SD among 12 evaluable patients (Fig 1). Extrahepatic metastases were removed in five patients after the immunoembolization of the liver metastases. Among these patients, two developed a significant immune response in the remote metastases (Fig 2). Based on this promising result, a phase II clinical trial is being designed. INTRALESIONAL GENE THERAPY TO ENHANCE AN IMMUNE RESPONSE
Direct delivery of a gene that stimulates the immune system has been tried.44 Rubin et al reported the result of the phase I study with direct gene transfer of an allogeneic histocompatibility antigen, HAL-B7.44 Under ultrasound guidance, liver metastases from colorectal carcinoma were injected with a plasmid vector containing genes of HLA-B7 and 2-microglobulin. Among 15 evaluable patients, plasmid DNA was detected in 14 patients and there was no adverse event directly related to the study drug. However, there was no objective regression of injected or uninjected liver metastases. Five of 15 patients had SD for more than 100 days.
CONCLUSION
Locoregional immuno(bio)therapy is a reasonable approach for metastatic liver tumors that are otherwise resistant to standard treatments such as chemotherapy. This approach can result in local control of the disease as well as establishment of systemic immune response to tumor cells. However, the number of patients in the past studies is small and treatment modalities were too variable to develop a sound consensus on this approach. In the future, clinical trials must be of a larger scale to adequately define the efficacy of locoregional immunotherapy for metastatic tumors in the liver. REFERENCES 1. Lygidakis NJ, Stringaris K, Kokinis K, et al: Locoregional chemotherapy versus locoregional combined immuno-chemotherapy for patients with advanced metastatic liver disease of colorectal origin: A prospective randomized study. Hepatogastroenterology 43:212-220, 1996 2. Okuno K, Kaneda K, Yasutomi M: Regional IL-2-based immunochemotherapy of colorectal liver metastases. Hepatogastroenterology 46:1263-1267, 1999 3. Okino T, Kan N, Nakanishi M, et al: The therapeutic effect of OK-432-combined adoptive immunotherapy against liver metastases from breast cancer. J Cancer Res Clin Oncol 116:197-202, 1990 4. Libutti SK, Bartlett DL, Fraker DL, et al: Technique and results of hyperthermic isolated hepatic perfusion with tumor necrosis factor and melphalan for the treatment of unresectable hepatic malignancies. J Am Coll Surg 191:519-530, 2000 5. Malter M, Friedrich E, Suss R: Liver as a tumor cell killing organ: Kupffer cells and natural killers. Cancer Res 46:30553060, 1986 6. Seki S, Abo T, Masuda T, et al: Identification of activated T cell receptor ␥␦ lymphocytes in the liver of tumor-bearing hosts. J Clin Invest 86:409-416, 1990 7. Bouwens L, Marinelli A, Kuppen PJ, et al: Electron microscopic observations on the accumulation of large granular lymphocytes (pit cells) and Kupffer cells in the liver of rats treated with continuous infusion of interleukin-2. Hepatology 12:1365-1370, 1990 8. Bouwens L, Jacobs R, Remels L, et al: Natural cytotoxicity of rat hepatic natural killer cells and macrophages against a syngeneic colon adenocarcinoma. Cancer Immunol Immunother 27:137-141, 1988 9. Gennari L: Liver metastases: A many-sided therapeutical problem. Hepatogastroenterology 39:5-9, 1992 10. Hohenberger P, Schlag P, Schwarz V, et al: Tumor recurrence and options for further treatment after resection of liver metastases in patients with colorectal cancer. J Surg Oncol 44:245-251, 1990 11. Bozetti F, Bignami P, Morabito A, et al: Patterns of failure following surgical resection of colorectal cancer liver metastases. Ann Surg 205:264-269, 1987 12. Patel K, Sullivan K, Aoyama T, et al: Hepatic artery chemoembolization (HAC) with BCNU for treatment of metastatic uveal melanoma. Proc Am Soc Clin Oncol 20:356, 2001 (abstr)
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30. Komatsu T, Yamauchi K, Furukawa T, et al: Transcatheter arterial injection of autologous lymphokine-activated killer (LAK) cells into patients with liver cancers. J Clin Immunol 10:167-174, 1990 31. Hennemann B, Scheibenbogen C, Schumichen C, et al: Intrahepatic adoptive immunotherapy with autologous tumorcytotoxic macrophages in patients with cancer. J Immunother 18:19-27, 1995 32. Satoh K, Kan N, Okino T, et al: The therapeutic effect of OK-432-combined adoptive immunotherapy against liver metastases from gastric and colorectal cancers. Biotherapy 6:41-49, 1993 33. Yamasaki S, Okino T, Kan N, et al: Factors influencing the response and survival of patients with liver metastases from breast cancer receiving OK-432-combined adoptive immunotherapy. J Cancer Res Clin Oncol 118:157-162, 1992 34. Kan N, Yamasaki S, Kodama H, et al: Bone metastasis as a prognostic factor in breast cancer patients with liver metastasis given OK-432-combined adoptive immunotherapy via the hepatic artery. Biotherapy 6:245-250, 1994 35. Ferlazzo G, Scisca C, Iemmo R, et al: Intralesional sonographically guided injections of lymphokine-activated killer cells and recombinant interleukin-2 for the treatment of liver tumors: A pilot study. J Immunother 20:158-163, 1997 36. Kasugai H, Kojima J, Tatsuta M, et al: Treatment of hepatocellular carcinoma by transcatheter arterial embolization combined with intraarterial infusion of a mixture of cisplatin and ethiodized oil. Gasteroenterology 97:965-971, 1989 37. Mavligit GM, Charnsangavej C, Carrasco H, et al: Regression of ocular melanoma metastatic to the liver after hepatic arterial chemoembolization with cisplatin and polyvinyl sponge. JAMA 260:947-976, 1988 38. Carrasco CH, Charnsangavej C, Ajani J, et al: The carcinoid syndrome: Palliation by hepatic artery embolization. AJR 147:149-154, 1986 39. Daniels J, Pentecost M, Teitelbaum G, et al: Hepatic artery chemoembolization (HAE) for carcinoma of colon using angiostat collagen and cis-platin, mitomycin, and doxorubicin: response, survival, and serum drug levels. Proc Am Soc Clin Oncol 11:171, 1992 (abstr) 40. Mavligit GM, Zukwiski AA, Ellis LM, et al: Gastrointestinal leiomyosarcoma metastatic to the liver. Cancer 75: 2083-2088, 1995 41. Kannai T, Monden M, Sakon M, et al: New development of transarterial immunoembolization (TIE) for therapy of hepatocellular carcinoma with intrahepatic metastases. Cancer Chemother Pharmacol 33:S48-S54, 1994 (suppl) 42. Sato T, Terai M, Huandong Y, et al: Systemic immune response after immunoembolization of liver metastasis with granulocyte-macrophage colony stimulating factor (GM-CSF). Proc Am Assoc Cancer Res (in press) 43. Aoyama T, Sullivan K, Terai M, et al: Immunoembolization of malignant liver tumors with granulocyte macrophage colony stimulating factor (GM-CSF) and ethiodized oil followed by gelatin sponge pledgets. Proc Am Soc Clin Oncol (in press) 44. Rubin J, Galanis E, Pitot HC, et al: Phase I study of immunotherapy of hepatic metastases of colorectal carcinoma by direct gene transfer of an allogeneic histocompatibility antigen, HLA-B7. Gene Ther 4:419-425, 1997