Cytokine-based biotherapy of gastrointestinal tumors

Clin Investig (1994) 72:526-534

C~inieN Ptlarmeee~egy Review Olinical

Investigator © Springer-Verlag 1994

Cytokine-based biotherapy of gastrointestinal tumors J. Buer 1, H. Kirchner t, A. Schomburg 1, A. Schiller 2, M. Manns 2, E. Lopez-H/inninen 1, S. Duensing 1, H. Poliwoda 1, J. Atzpodien 1

Abteilung H/imatologie und Onkologie, Medizinische Hochschule Hannover, D-30623 Hannover, Germany 2 Abteilung Gastroenterologie und Hepatologie, Medizinische Hochschule Hannover, D-30623 Hannover, Germany

Received: 30 July 1993 / Returned: 22 November 1993 / Accepted: 18 April 1994

Abstract. Over the past 20 years the administration of cytokines has emerged as an important fourth modality for the treatment of human cancer. Ad- vances in the field of therapy of gastrointestinal tumors have become a major focus of current re- search, given the lack of progress of conventional antineoplastic therapy in most of these tumors. Among the heterogeneous group of gastrointestinal malignancies, novel therapeutic strategies have been employed for each individual tumor type, and cytokines (interferon-00 have gained an established role in the treatment of advanced carcinoid tumors. Although our understanding of the mechanisms of biological response modification is still limited, further improvement in the management of gastrointestinal malignancies can be expected from multimodality therapy regimens employing cytokines in combination with other biological response modifiers, chemotherapeutic agents, active-specific immunotherapy, and immunotoxin- and radionu- clide-conjugated monoclonal antibodies. A wide range of clinical and preclinical studies have been conducted in colorectal carcinoma; however, potential therapeutic benefit of cytokine-based biotherapy has not been fully defined. Therefore, large- scale, i.e., multicenter, studies are required to quan- tify the potential therapeutic effects of cytokines in gastrointestinal tumors.

Key words: Gastrointestinal tumors - Cytokine - Biotherapy - Interferon-~ - Interleukin-2

Over the past two decades, the use of biological agents has been introduced to the therapy of human cancer. The term biological response modifiers is used to suggest that these agents function by

Abbreviations: FA = folinic acid; 5-FU = 5-fluorouracil; GI = gastrointestinal; HCC = hepatocellular carcinoma; IFN = interferon; IL = interleukin; LAK cells = lymphokine- activated killer cells; TNF = tumor necrosis factor Correspondence to: J. Atzpodien

altering the host response to cancer rather than by direct cytotoxicity. Recent progress in the field of biotechnology has allowed the production of highly purified cytokines in sufficient quantity to assess clinical usefulness. Although biological therapy is still in its infancy, there are many examples ofsuc- cesful administration of biological therapy to human cancer, reviewed by DeVita and colleagues [19]. While overall progress in the conventional systemic therapy of gastrointestinal (GI) malignancies has been slow, the promise of systemic immunotherapy in GI tumors is substantiated by the challenging concept of activating the host's immune system toward a highly specific in vivo antitumor response.

Cytokines as single agent

Cytokines are a group of intercellular messenger proteins that are key immunoregulatory com- pounds. They are involved in the pathophysiology of various human diseases. They comprise the largest group of biological response modifiers in clinical trials and include the interferons (IFN-~, IFN-[3, IFN-y), interleukins (ILl-ILl3), and hema- topoietic growth factors [19]. The most frequently administered recombinant cytokines in the therapy of GI tumors are INF-~ , IL-2, and INF-% while the clinical experience with other biological response modifiers including tumor necrosis factor-~ (TNF-~) and IL-1 is overall limited. While human INFs and TNF have been shown to exert direct antiproliferative activity against various GI cancers, IL-2 affects tumor proliferation solely through the induction of secondary immune functions, both humoral and cellular [19, 75, 77, 99].

Assessing clinical usefulness of these agents has been difficult since the paradigms for cytotoxic chemotherapy are generally inappropriate for cytokines. The optimal biological response is often not found at maximal tolerated dose. Rather, cytokines usually demonstrate peak activity within a

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dose range whereby both higher and lower concentrations may result in suboptimal effect [6, 14, 81]. Thus, the optimal dose clinically is to be defined as one which produces the maximum effect, not the highest dose tolerated without unacceptable toxicity. Previously, single agent cytokine therapy has been investigated; however, this modality rarely produced significant antitumor activity in GI malignancies other than carcinoid tumors (Tables 1- 5). Therefore the immunomodulatory and antiproliferative effects of biological response modifiers were most widely exploited in combination thera- pies with other immunomodulating or conventional chemotherapeutic agents, and a plethora of clinical studies has been reported.

Preclinical studies determining IFN-~ and 5-fluorouracii synergism

As combination chemotherapy has an established role in the management of various malignancies, the combination of conventional cytotoxic drugs with biological response modifiers is also highly reasonable considering the nonoverlapping mechanisms of action and toxicity spectra of these agents. The most extensive preclinical experience with cytokine/chemotherapy combinations has been gained with 5-fluorouracil (5-FU) and IFN-~, which is also the best studied and most frequently used combination in clinical practice [98]. In addition to the separate antiproliferative actions of IFN-~ and 5-FU, various modes of action have been hypothesized for the potential synergy of these agents: (a) improved 5-FU efficacy through IFN-~ mediated inhibition of thymidylate syn- thetase induction [15, 25]; (b) increased formation of active 5-FU metabolites in cells exposed to IFN-

[25]; (c) reversal of IFN-~ related suppression of tumor susceptibility toward autologous natural killer cells after pretreatment with 5-FU [52, 73]; (d) altered pharmacokinetics of 5-FU, i.e., reduced clearance and increased toxicity upon addition of IFN-~ [82]; (e) protection of normal host tissue by IFN-~, allowing for a dose intensification of 5-FU [87].

Despite this body of preclinical evidence it remains unclear whether IFN-~ affects the therapeutic efficacy of 5-FU via direct immunomodulation or through biochemical pathways as in combinations of 5-FU with levamisole, folinic acid (FA), and N-(phosphonacetyl)-L-aspartate. Further- more, a deeper understanding of the mechanisms of action is needed to clarify not only the optimal choice of the combination agent, but also the drug concentrations, ratios, durations, and sequence of

administration of different agents. The multifacto- rial effects and nonlinear dose-response curves of biological response modifiers further add to the complexity of cytokine combination therapy [76, lOOl.

Clinical trials in gastrointestinal tumors

GI tumors constitute a heterogeneous group of different malignancies, and clinical investigations studying the effect of immunotherapy in cancers of the esophagus, the liver, and of the biliary system are sporadic. Following early results by other investigators [51, 88], Kelsen et al. reported a 25% response rate in advanced esophageal cancer patients treated with a combination of IFN-~2a and 5-FU [42].

Hepatocellular carcinoma (HCC) is one of the most common cancers in the world. A number of chemotherapeutic agents have been evaluated for the treatment of HCC. However, most of these treatment protocols were associated with significant side effects and, at best, resulted in an overall survival of several months. Immunotherapy of HCC primarily involved radiolabeled antiferritin antibodies without the concomitant use of cytokines [64, 92]; further immunotherapy trials in HCC included IFN-~ alone [93] or in combination with various agents such as 5-FU [65, 66], doxorubicin [50], and cyproterone acetate [40]; IL-2 in combination with lymphokine-activated killer cells [46] and adriamycine [41] has also been administered to HCC patients, with limited efficacy. In addition, single-agent IFN-~ has been used effectively in the treatment of chronic liver disease induced by hep- atitis B and C viruses, both of which are thought to play an important role in the etiology of HCC [19].

A limited number of clinical trials has been conducted in patients with advanced gastric carcinoma (Table 1). Most investigators have employed combinations of IFN-~ and 5-FU, with response rates ranging from 0% to 34%; other agents include IL- 2 and nonspecific irnmunostimulants, with no response reported. Recently there has been much focus on monoclonal antibodies directed at highly restricted and more uniformly expressed tumor-associated antigens [771. These antibodies are selected by their ability to effectively induce antibody-de- pendent cell-mediated cellular cytotoxicity, which is potentiated by IL-2 and macrophage colony- stimulating factor [58].

The majority of biotherapy studies in pancreatic tumors, including neuroendocrine tumors (carcinoids, islet cell tumors, and other tumors of the amine and precusor uptake and decarboxylation

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Table 1. Selected biotherapy and biochemotherapy studies in gastric carcinoma

Reference Agents n No. of 95% CI Response responders duration

(months)

Nio et al. [59] OK-432 a 6 NR - - Takekoshi et al. [ 1 0 ] OK-432, IFN-7,5-FU, MMC, ADM, CDDP 1 1 NR Arinaga et al. [4] Lentinan u 15 NR - -

Gomez et al. [29] IFN-%a, 5-FU 32 11 19-53% 14+ Iaffaioli et al. [36] IFN-cz, 5-FU, CBDCA, EPI 19 -° - -

Lee et al. [49] I F N - ~ z b , 5-FU 13 4 9-61% 6-28 Pazdur et al. [67] IFN-~2~ , 5-FU 40 10 13-41% 13 J/iger-Arand et al. [38] IFN-~, 5-FU, FA 36 17 NR 5.5 + Modiano et al. [56] IFN-c~, 5-FU, FA, etoposide 4 1 NR NR

Merrouche et al. [54] IL-2, BCNU, auBMT 14 3 5-51% 8 85 Ubhi et al. [94] IL-2, 5-FU 4 _a _

FA, Folinic acid; CBDCA, carboplatinum; EPI, epidoxorubicin; BCNU, carmustine; auBMT, autologous bone marrow transplantation; MMC, mitomycin-C; ADM, Adriamycin; CDDP, cisplatinum; NR, not reported

Picibanil, a preparation from Streptococcus pyogenes used for biological response modification b An immunopotentiating polysaccharide from extracts of mushroom Lentinus edodes c Neoadjuvant setting in locally advanced carcinomas; in 13 previously inoperable patients subsequent gastrectomy was possible a Patients after potentially curative surgery in the adjuvant setting

Table 2. Selected biotherapy and biochemotherapy studies in neuroendocrine and other pancreatic tumors

Reference Classification a Agents n No. of 95% CI Response responders duration

(months)

DiBartolomero et al. [21] Dirix et al. [22] Oberg and Erikson [61] Biesma et al. [8] Sch6ber et al. [80] Creutzfeld et al. [16] Derderian et al. [18] Knuth et al. [44] Modiano et al. [56] Sporn et al. [84] Schmiegel et al. [78] VonHoff et al. [96] Weiner et al. [103] Brown et al. [11]

Neuroendocrine Neuroendocrine Neuroendocrine Neuroendocrine Neuroendocrine Neuroendocrine Carcinoma Carcinoma Carcinoma Carcinoma Carcinoma Carcinoma Carcinoma Carcinoma

IFN-~2a 20 2 1-32% NR IFN-~2b 11 3 6-61% NR IFN-~2b 111 17 b 9-24% 34 IFN-~eb 20 2 1-32% NR IFN-e2b 26 4 4-35% NR IFN-%o 15 0 ° 0-22% - IFN-~2a, 5-FU 46 3 1-18% 5-15 IFN-~2,, 5-FU, FA 13 3 5-54% 4+ IFN-~2,, 5-FU, 7 6 NR NR IFN-%a, 5-FU, FA, cisplatin 11 5 NR 3-21 TNF-~ 15 0 0-22% IFN- 7 30 0 0-12% MoAb 17-1A 16 0 0-21% Taxol, G-CSF 20 5 0-17% NR

FA, Folinic acid; MoAb, monoclonal antibody; G-CSF, granulocyte colony-stimulating factor; NR, not reported a Malignant carcinoid tumors and islet cell tumors are neuroendocrine tumors considered to originate from the neural crest u Oberg et al. also reported a significant decrease in hormone secretion in 47 patients c Creutzfeld et al. also reported a significant decrease in hormone secretion in 7% of patients

system), a n d p a n c r e a t i c c a r c i n o m a s (Table 2), have used I F N - ~ a lone or in c o m b i n a t i o n wi th c h e m o t h e r a p e u t i c agents , i.e., 5 - F U wi th or wi th- ou t fol inic acid. W h i l e there were s ign i f ican t responses ( 0 % - 2 7 % ) in n e u r o e n d o c r i n e t u m o r s , p a n - creat ic c a r c i n o m a s a p p e a r to be overa l l r e f rac to ry to I F N - ~ . In a d d i t i o n , s ing le -agen t I F N - 7 , T N F - ~ , a n d the 1 7 - 1 A m o n o c l o n a l a n t i b o d y have b e e n ad-

m i n i s t e r e d to p a n c r e a t i c t u m o r pa t i en t s wi th no s u b s e q u e n t ob jec t ive response .

Colorec ta l cancer

C u r r e n t t h e r a p y for a d v a n c e d co lorec ta l c a r c i n o m a us ing 5 - F U , the m o s t act ive single agen t p r o d u c e s r e sponse ra tes of less t h a n 2 0 % a n d does n o t inf lu-

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Table 3. Selected I F N ~ / 5 - F U based biotherapy in colorectal carcinoma ~

Reference Agents b n No. of 95% CI Pretreated responders patients

Wadler et al. [98] IFN-¢~, 5-FU (CIVI, IV) 17 13 50 93% 0 Wadler and Wiernik [97] IFN-cx, 5-FU (CIVI, IV) 32 23 53-86% 0 Douillard et al. [23] IFN-cq 5-FU (CIVI, IV) 16 5 11-59% 0 Hubermann et al. [35] IFN-eq 5-FU (CIVI, IV) 33 13 23-58% 0 Jaiyesimi et al. [39] IFN-eg 5-FU (CIVI) 23 4 5-39% 0 Wadler [100] IFN-c~, 5-FU (CIVI, IV) 36 15 26-59% 0 Weh et al. [101] IFN-c~, 5-FU (CIVI, IV) 40 12 17-47% 0 Diaz-Rubio et al. [20] IFN-c~, 5-FU (CIVI, IV) 33 8 11 42% 0 Kemeny et al. [43] IFN-~, 5-FU (CIVI, IV) 38 9 11-40% 0 Pazdur et al. [68] IFN-~, 5-FU (CIVI, IV) 45 16 22-51% 0 Brunetti et al. [11] IFN-c~, 5-FU (IV) 18 4 6-48% 14% Hansmann et al. [32] IFN-~, 5-FU (2-h CIVI), FA 19 2 1-33% 100% Nobile et al, [60] IFN-c~, 5-FU (IV), FA 41 6 6-29% 63% Piedbois et al. [69] d IFN-e~, 5-FU (2-h CIVI), FA 16 8 25 75% 38% Bukowski et al. [12] IFN-¢~, 5-FU (IV), FA 55 15 16-41% 0 Cascinu et al. [13] IFN-~, 5-FU (IV), FA 45 23 36-66% NR K6hne-W6mper et al. [45] IFN-~, 5-FU (IV), FA 21 6 9-49% 0 Kreuser et al. [47] IFN-cx, 5-FU (4-h CIVI), FA 45 14 18-47% NR Labianca et al. [48] IFN-cc, 5-FU, FA 16 4 8-55% NR Preiss [70] IFN-e~, 5-FU, (24-h CIVI), FA 23 9 20-61% 0 Schmoll et al. [71] IFN-c~, 5-FU (2-h CIVI) 32 3 2-25% 0 Sobrero et al. [83] IFN-c~, 5-FU, FA 44 6 5 27% NR Punt et al. [71] IFN-e~, 5-FU (CIVI), FA 44 11 12-38% 0 Steger et al. [85] IFN-¢~, 5-FU (2-h CIVI), FA 32 9 15-49% 0 Mattioli et al. [53] IFN-c~, 5-FU, mitomycin-C 20 6 12-54% NR Hansen et al. [31] IFN-e~, 5-FU, dipyridamole 15 6 16 68% NR Zaniboni et al. [105] IFN-e~, 5-FU, FA, dipyridamole 26 11 23-63% NR Findlay et al. [26] ~ IFN-e~, 5-FU (CIVI) 118 38 25-41% 52%

FA, Folinic acid; NR, not reported a Only clinical trials comprising more than 15 patients were selected for presentation b Mode of 5-FU application: IV, intravenous bolus; CIVI, continuous intravenous infusion ° In previously untreated patients Nobile et al. observed a response rate of 34.3% a In previously untreated patients Piedbois et al. reported a response rate of 70% e IFN-¢~ was added at the time when tumor became refractory to 5-FU; in previously untreated patients Findlay et al. observed a response rate of 42%

ence patient survival. Given the high prevalence of colorectal cancer, recent clinical and preclinical re- search in immunotherapy has focused on this tumor. Results of immunochemotherapy regimens in patients with advanced colorectal cancer are shown in Tables 3-5.

Following early reports by Wadler and colleagues [98], who achieved a response rate of 76% in 17 metastatic disease patients treated with IFN- ~/5-FU as first-line combination therapy, substan- tially lower response rates in advanced colorectal cancer patients were found in multicenter confir- mation trials [43, 68]. However, overall response rates (Table 3) appeared slightly superior to those reported previously with 5-FU based chemotherapy alone; however, a significant survival benefit after combined 5-FU/IFN-~ biochemotherapy has not been demonstrated. Given the wide variety of treatment schedules (e.g., intravenous bolus vs.

continuous intravenous infusion 5-FU, additional FA), patient inclusion criteria (e.g., chemotherapy pretreatment) and reported response rates, further prospective randomized trials are needed.

In addition, a plethora of divergent and rather nonspecific immunomodulators have been employed in colorectal carcinoma patients (Table 4), notably IL-1[3, IFN-7, and TNF; no significant antitumor effect has been observed.

Interleukin-2 based clinical studies

In contrast, interleukin-2 based immunotherapy and combined IL-2 biochemotherapy have been consistently studied in advanced colorectal carcinoma patients in a large number of trials. Follow- ing early investigations employing IL-2 single- agent therapy with additional retransfusion of

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Table 4. Selected biotherapy and biochemotherapy studies in colorectal carcinoma

Reference Agents n No. of 95% CI responders

Nio et al. [59] OK-432 a 5 NR - Monden et al. [57] OK-432, fibrinogen b 20 NR - Takagi et al. [89] OK-432, TNF 66 15 13-35% Gabrilove et al. [27] IL-l[3, 5-FU NR N R - Crown et al. [17] IL-I~, 5-FU 18 NR - O'Connell et al. [62] IFN-y 31 1 0-17% Weiner et al. [102] IFN-y, MoAb 17-lA 25 0 0-14% Ajani et al. [2] IFN-y, 5-FU 29 2 1-23% Abbruzzese et al. [1] IFN-y, TNF 13 0 c 0-25% Blottiere et al. [9] IFN-y, tumor-binding MoAb mixture 15 N R - Tsugita et al. [94] Autologous LAK cells 18 0 d 0-19% Saleh et al. [77] MoAb D612 e 21 0 NR

FA, Folinic acid; MoAb, monoclonal antibody; NR, not reported a Picibanil, a preparation from Streptococcus pyogenes used for biological response modification b Intratumoral injection prior to surgery c Early trial termination due to excessive toxicity a Tsugita et al. reported one minor remission e This is the first trial of a monoclonal antibody directed to a gastrointestinal-specific tumor-associated antigen

Table 5. Selected interleukin-2 based biotherapy and biochemotherapy studies in colorectal carcinoma

Reference IL-2 a Additional n No. of 95% CI agents responders

Hayakawa et al. [33] CIAI - 9 0 0-34% Atzpodien et al. [5] SC - 4 0 ~ 6 0 % Israel et al. [37] CIVI - 13 0 0-25% Rosenberg et al. [74] IV LAK cells 26 3 2-30% West et al. [104] CIVI LAK cells 13 0 0-25% Mittelman et al. [55] IV LAK cells 8 0 0-37% Rosenberg et al. [75] IV LAK cells 30 5 6-35% Steis et al. [86] IV, IP LAK cells (IP) 12 b 5 15-72% Mittelman et al. [55] CIVI IFN-~, (IM) 7 0 0-41% Rosenberg et al. [75] IV IFN-~, (IV) 9 1 0 4 8 % Atzpodien et al. [6] SC IFN-~, (SC) 8 0 0-37% Hamblin et al. [30] CIVI 5-FU 5 2 5-85% Hayakawa et al. [33] CIAI Cyclophosphamide 9 3 7-70% Hiddemann et al. [34] CIVI 5-FU, FA 22 3 c 3-35% Arinaga et al. [3] IV Mitomycin 33 10 16-49% Atzpodien et al. [7] SC IFN-~z, 5-FU 14 4 8-58% Taleghani et al. [91] SC IFN-~, 5-FU, FA 4 2 7-93% Ziegler et al. [106] SC MoAb L6 5 1 0-52%

FA, folinic acid; MoAb, monoclonal antibody a Mode of IL-2 application: IV, intravenous bolus; CIVI, continuous intravenous infusion; IP, intraperitoneal; SC, CIAI, constant intraarterial infusion; IM, intramuscular b Patients with disease limited to the peritoneal cavity only ° Hiddemann et al. also reported five minor remissions

subcutaneous;

lymphokine-activated killer (LAK) cells, the majority of recent studies employed combinations of IL- 2, IFN-~ and/or 5-FU. By combining 5-FU with IL-2, 5-FU has shown to potentiate the effect of IL-2 on LAK cell induction, with significant eleva- tion in LAK cell generation following some days after 5-FU infusion [63]. These data provide a ra-

tionale for the sequential use of 5-FU followed by IL-2 for the boost of circulating immune cells and subsequent enhancement of tumor cell lysis. Unfor- tunately, the clinical results of such an approach have been disappointing. In a series of 14 patients with metastatic colorectal cancer treated in this manner, objective response was only observed in

531

one pat ient ; toxicity remained significant, and no p ro longa t ion of survival was achieved [72].

In a clinical s tudy using a triple combina t i on of IL-2, IFN-~ , and 5 -FU in advanced colorectal cancer pat ients an objective response rate of 28% was observed [7], which was not substant ia l ly different f rom results r epor ted with 5-FU, 5 - F U / I F N - ~ or 5 - F U / F A . Overall , the therapeut ic efficacy of IL-2 based b io the rapy in colorectal c a r c inoma pat ients has not yet been established.

Conclusions and future directions

The therapeut ic role of IF N-~ , IL-2, and other biological response modifiers in single-agent and in b i o c h e m o t h e r a p y combina t i on trials of advanced G I ca rc inoma pat ients remains mos t ly exper imen- tal. Cons t i tu t ing a safe and well- tolerated treat- men t modal i ty , I F N - ~ as single agent has a defined role in the pal l ia t ion and s y m p t o m a t i c the rapy of advanced carcinoids. In mos t G I mal ignancies further clinical studies are required, given the expected potent ia l of mu l t imoda l cancer the rapy involving cytokines and growth factors, active-specific im- m u n o t h e r a p y with vaccines or ant i - idiotypic antibodies, as well as passive i m m u n o t h e r a p y with radiolabeled m o n o c l o n a l ant ibodies such as anti- TAG-72 . In summary , i m m u n o t h e r a p e u t i c management of pat ients with refractory G I tumors has a proven, yet limited, efficacy and is still in its infancy. Despi te our lack of in-depth unders tand ing of the therapeut ic mechan i sms of mos t cytokines, therapeut ic opt ions have substant ia l ly improved , and fur ther invest igat ions of cytokines and o ther biological response modifiers in G I mal ignancies will be evalua ted t oward the following end-points : (a) extended survival of t u m o r pat ients with no cu- rat ive opt ions ; (b) quali ty of life upon and after the rapy ; and (c) p ro longa t ion of relapse-free inter- vals in the ad juvan t setting. Therefore enrol lment of pat ients into control led clinical trials using biological response modifiers in G I tumors is to be encouraged.

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