- Email: [email protected]
Immunotherapy for metastatic renal cell carcinoma: is it a therapeutic option yet?
symposium article
Annals of Oncology 18 (Supplement 6): vi149–vi152, 2007 doi:10.1093/annonc/mdm245
Immunotherapy for metastatic renal cell carcinoma: is it a therapeutic option yet? M. Guida* & G. Colucci Oncology Department, National Oncology Institute, Bari, Italy
introduction
cytokines
The management of metastatic renal cell cancer (MRCC) constituted a therapeutic challenge and no standard therapy has been established until few years ago. As known, RCC is a chemoresistant neoplasm with antiblastic agents inducing objective response only in a minority of patients. Recently, some multitarget-oriented drugs have shown an impressive activity in MRCC with a high percentage of partial response (PR) and/or stable disease (SD) and with a significant impact on survival [1, 2]. As known, RCC is one of the most immunoresponsive of human malignancies. Thus, immunotherapy remains one of the most important therapeutic options for these patients. The value of immunotherapy is its curative potential in some patients and its capability to obtain very durable responses as demonstrated by long-term follow-up [3, 4].
Interleukin 2 (IL-2), with or without lymphokine-activated killer cells, has demonstrated an important antitumoral activity in RCC. As single agent, IL-2 has been evaluated in various dose and treatment schedules yielding a response rate of 10%–23% [5, 6]. As the initial i.v. use of this cytokine was associated with severe toxicity requiring even intensive care support, several studies were initiated to evaluate the efficacy of IL-2 given s.c. This IL-2 administration modality seems to provide therapeutic efficacy similar to that reported for i.v. IL-2 while drastically reducing treatment-related toxicity to the point of even permitting outpatient care and self-administration [7]. However, the response rate and duration seem to be longer with high-dose IL-2 with respect to low dose [8]. Some authors recently have also reported a better survival for high-dose IL-2 [9]. When IL-2 was used in association with interferon (IFN), the results were quite similar, while toxicity was significantly enhanced [9].
*Correspondence to: Dr M. Guida, via Amendola 209, 70122 Bari, Italy. Tel: +39 080 5555239; Fax: +39 080 5555239; E-mail: [email protected]
ª 2007 European Society for Medical Oncology
symposium article
Downloaded from http://annonc.oxfordjournals.org/ at East Tennessee State University on June 16, 2015
Until 1 year ago, immunotherapy was considered the standard treatment of metastatic renal cell carcinoma (MRCC) producing objective response of 10%–20% and an overall survival of 1 year. Recently, some multitarget-oriented drugs have shown an impressive activity in MRCC with a high percentage of partial response and/or stable disease with a significant impact on survival. Nevertheless, immunotherapy remains another important therapeutic option for these patients. The value of immunotherapy is its curative potential in some patients and its capability to obtain very durable responses as demonstrated by long-term follow-up. Interesting results seem obtained also when immunotherapy is used in combination with some chemotherapeutic agents. Gemcitabine demonstrated be a good drug to combine with immunotherapy because of its little detrimental effects on cellular immunity. In phase II studies, interesting results have been reported. We treated 41 patients with MRCC using a biweekly schedule including s.c. interleukin 2 (IL-2), gemcitabine and vinorelbine. The overall response was 40% and the median survival was 24 months. Treatment was well tolerated and easily manageable. Vaccines are another promising treatment of RCC intended to stimulate a specific antineoplastic response. Vaccines have been explored both in an adjuvant and in a metastatic setting. We started a pilot study with dendritic cells vaccine loaded with autologous tumor in MRCC. The treatment has resulted feasible, well tolerated and effective in a minority of patients. In the future, combination immunotherapy with multitarget-oriented drugs may be one way forward. Also advances in cellular therapies and new immunomodulatory molecules as monoclonal antibodies are producing new therapeutic options. Finally, the identification of a panel of prognostic factors could provide an important tool to guide the choice of treatment of patients with a different risk profile. Therefore, the increasing therapeutic options for RCC should be seen not as a competition among the different treatments but as an expanding armamentarium available for these patients. Key words: chemoimmunotherapy, metastatic renal cell carcinoma, vaccine
symposium article
Annals of Oncology
chemoimmunotherapy Preclinical studies showed synergic-additive effects when immunotherapy is used in combination with some chemotherapeutic agents. Initially, improved results were reported with an association of chemotherapy plus IFN. However, randomized studies demonstrated only a small increase in overall response with no difference in survival [10, 11]. More recently, Atzpodien et al. [12] reported in a large randomized trial high percentage of responses (31%) and a very long survival (25 months) with the combination of s.c. IL-2 plus IFN-a and 5-flurouracil (5-FU) with respect to vinblastine and IFN-a. On the contrary, the addition of 13-cis-retinoic acid does not increase the results. Although encouraging, these results need further confirmatory studies. In our first experience with low-dose s.c. IL-2, IFN-a and vinblastine, we reported in 23 patients with MRCC 21.6% of overall response and a 65% of SD. The median overall survival was 11months, with 27 months for responders, 11 months for patients with SD and 8 months for patients with rapid progression [13].
experiences with gemcitabine plus immunotherapy Preclinical data showed that gemcitabine (GEM) could be a good drug to combine with immunotherapy. In fact, it has been demonstrated that IFN-a increases the cytotoxicity of GEM and the tumor responses of human RCC in xenografts [14]. Moreover, GEM seems to exert a selective detrimental effect on the humoral immune response but not on specific antitumor cellular immunity. It has also been reported that weekly short infusions of GEM are not associated with reduction of CD4/CD8 ratio and natural killer cell in patients with solid tumors [15]. In Table 1 are reported the principal experiences with GEM used without and in association with immunotherapy in MRCC. The efficacy of GEM alone [16] in chemotherapy-naive Table 1. Principal studies with gemcitabine in metastatic renal cell carcinoma Authors De Mulder et al. [16] Rini et al. [17] Rohde et al. [18]
No. of patients 39 39* 9**
Ryan et al. [19]
41
Neri et al. [20]
15
Guida et al. [21]
45
Treatment 2
GEM 800 mg/m , g 1, 8, 15 GEM 600 mg/m2, g 1, 8, 15 5-FU c.i. 150 mg/m2/days 1–21 GEM IFN-c GEM 5-FU c.i. IL-2 s.c. + IFN-a GEM IL-2 s.c. + IFN-a GEM Navelbine IL-2 s.c. + IFN-a
OR/CR (%)
TtP/OS (months)
8.1/2.5 17/O
OS 12.3 TtP 7
15/0
OS 13.5
14.6
6.6/20.6
28
14/20
40/6.6
OS 24
CR, complete response; TtP, time to progression; OR, overall response; OS, overall survival; GEM, gemcitabine; 5-FU, 5-fluorouracil; IL-2, interleukin 2; c.i., continuous infusion; IFN, interferon.
vi150 | Guida & Colucci
Volume 18 | Supplement 6 | June 2007
Downloaded from http://annonc.oxfordjournals.org/ at East Tennessee State University on June 16, 2015
MRCC has been explored in a phase II study and a response rate of 8% has been reported with a survival >12 months. Better results have been obtained when GEM was associated with other chemotherapeutic agents [17, 22, 23]. The association of GEM plus immunotherapy has been minimally explored. Rohde et al. [18] reported the results on nine patients pretreated with immunotherapy using GEM and IFN-c. The response was 15% and the overall survival was 13.5 months. Ryan et al. [19] in 41 patients, treated with GEM plus 5-FU continuous infusion, IFN-a and low dose of IL-2 given s.c., reported an overall response of 14.6% and an overall survival of 20.6 months. Neri et al. [20] using GEM in association with s.c. IL-2 and IFN-a in 15 untreated patients reported an overall response of 28%, with a time to progression and survival lasting 14 and 20 months, respectively. We explored the efficacy and tolerability of a schedule including low-dose s.c. IL-2 in association with GEM and vinorelbine (VRB) in a phase II trial using a biweekly schedule in patients with MRCC [21]. Forty-five patients were included in the study. The following schedule was used: IL-2 at 4.5 million IU daily from day 1 to day 4; GEM 1200 mg/m2 on day 1 and VRB 25 mg/m2 on day 1. Therapy was recycled every 14 days. The overall response was 40% with three patients (6.6%) obtaining a complete response (CR) and 15 (33.3%) PR; 13 (29%) experienced a SD and 14 (31%) progressed. Response occurred not only in soft tissue/lymph nodes (35%) and lung/pleural (30%) disease but also in bone/visceral (35%) disease. Median response duration was 20 months, 34+ for CR and 24 for PR. Median survival was 24 months, 27 for CR/PR/SD and 8 for progressive patients. Treatment was well tolerated and easily manageable. IL-2 was mainly administered as outpatient care. Most relevant toxicity was chemotherapy related with grade 1–2 neutropenia being most common. IL-2-related toxicity was as expected and completely reversible with stopping therapy. In summary, we demonstrated that biweekly GEM–VRB plus low-dose IL-2 is a feasible and effective regimen in MRCC with a good toxic profile. On the basis of the present
Annals of Oncology
data, we are carrying out a large phase III trial comparing this schedule versus IL-2 immunotherapy alone.
vaccinetherapy
Volume 18 | Supplement 6 | June 2007
administered i.d. at a dose of 10 · 106 cells every 2 weeks for four times, followed by monthly administration in responding/SD patients until progression or vaccine availability. Low-dose IL-2 was also administered for 4 days after each vaccination. Until now, 17 patients have been treated (12 melanoma and 5 RCC). It was possible to prepare vaccine for all patients. The procedure, even though feasible, was elaborate and expensive. Compliance and tolerability were very high. No side-effects were registered, except IL-2-related side-effects. With regard to efficacy, we observed two PR (one MM and one MRCC; duration 12 and 3+ months, respectively), six SD (OS 8–4 months), one no evidence of disease for 14 months (MM with hepatic disease removed surgically), six PD and two not valuable (early). Although significant progress has been made in vaccine therapy, is still a long way to go.
conclusions RCC is one of the most immunoresponsive of human malignancies; thus, immunotherapy remains one of the most important therapeutic options for this neoplasm. Moreover, despite exciting results obtained with the advent of the new tyrosine kinase inhibitors, the value of immunotherapy is its curative potential in some patients and its capability to obtain very durable responses. Combination immunotherapy with multitarget-oriented drugs may be one way forward. Also the identification of a panel of prognostic factors could provide an important tool to guide the choice of treatment of patients with a different risk profile. Moreover, advances in cellular therapies, vaccines and new immunomodulatory molecules as monoclonal antibodies are producing new therapeutic options. Thus, the increasing choices available at present should be considered not as a competition among the different treatments but as an expanding armamentarium for the patients with MRCC.
references 1. Motzer RJ, Hutson TE, Tomczak P et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007; 356: 115–124. 2. Escudier B, Eisen T, Stadler WM et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007; 356: 125–134. 3. Yang JC, Childs R. Immunotherapy for renal cell cancer. J Clin Oncol 2006; 24: 5576–5583. 4. Parton M, Gore M, Eisen T. Role of cytokine therapy in 2006 and beyond for metastatic renal cell carcinoma. J Clin Oncol 2006; 24: 5584–5592. 5. 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 1987; 316: 889–897. 6. Dilman RO, Church D, Oldham RK et al. Inpatient continuous-infusion of interleukin-2 in 788 patients with cancer. The National Biotherapy Study Group experience. Cancer 1993; 71: 2358–2370. 7. Atzpodien MJ, Korfen A, Franks CR et al. Home therapy with recombinant interleukin-2 and interferon-2b in advanced human malignancies. Lancet 1990; 335: 1509–1512. 8. Yang JC, Sherry RM, Steinberg SM et al. Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer. J Clin Oncol 2003; 21(16): 3127–3132.
doi:10.1093/annonc/mdm245 | vi151
Downloaded from http://annonc.oxfordjournals.org/ at East Tennessee State University on June 16, 2015
Vaccines are a promising but still experimental treatment of RCC. This approach theoretically should permit the selective and safe destruction of the neoplastic cells because they are intended to stimulate a specific tumor-protective immune response against neoplastic cells that share some antigens contained in the administered vaccine [3, 24, 25]. Vaccines can stimulate both antibody and cellular response against tumor. The type of response induced, its frequency and its magnitude depend on vaccine construct and on the adjuvant used. Cancer vaccines can be grouped in cellular, anti-idiotype, peptide/protein based, glycolipid, and nucleic acid based. Immunological adjuvants can include not only the more classical ones (incomplete Freund’s adjuvant, alum, bacille Calmette–Guerin, QS-21) but also new molecules as cytokines [IL-2, IL-12 and granulocyte–macrophage colony-stimulating factor (GM-CSF)] or high purified immunogenic proteins cocktail (heat shock proteins) or dendritic cells (DCs). To date, it is unclear what is the best number of antigens required to induce a more effective and clinically relevant immune response. For these reasons, several authors prefer to use vaccines containing a broad array of antigens rather than single, highly purified antigen. The stimulation of immune response against multiple targets should increase the chances of killing neoplastic cells and minimize the chances that tumor cells will be able to down-modulate the expression of all the targeted antigens to avoid immune attack [24]. Clinical trials are shown that vaccines are safe to use and have much less toxicity than other current therapies. Moreover, a growing body of evidence indicates that vaccines can be clinically effective although in a minority of patients. The recent use of DCs loaded ex vivo with a wide variety of tumor antigens has increased the frequency of tumor-specific immune responses and clinical regressions [25]. Though clinical trials conducted so far remains unsatisfactory, numerous new findings and knowledge in basic immunology and molecular biology indicate that these results could be significantly improved in the next future [24]. In RCC, vaccine has been explored both in an adjuvant and in a metastatic setting. A randomized phase III trial using an autologous tumor cell vaccine versus no treatment has showed a significant advantage for patients treated versus the control arm in terms of both disease-free and overall survival [25]. Another large phase III trial using heat shock protein versus observation in patients with high-risk recurrence after surgical treatment is ongoing. In MRCC, several experiences have been made using different types of vaccine (neoplastic cell, heat shock protein, DC) with an overall response resulting in 10% [3]. We started a pilot study with DC generated from peripheral blood mononuclear cells obtained from leukapheresis procedure. After 6 days culture with IL-4 and GM-CSF, DCs were pulsed with autologous tumor lysate and matured with a cocktail of cytokines. Vaccine was
symposium article
symposium article
vi152 | Guida & Colucci
17. Rini BI, Vogelzang NJ, Dumas MC et al. Phase II trial of weekly intravenous gemcitabine with continuous infusion fluorouracil in patients with metastatic renal cell cancer. J Clin Oncol 2000; 18(12): 2419–2426. 18. Rohde D, Thiemann D, Wildberger J et al. Treatment of renal cancer patients with gemcitabine (2#,2#-difluorodeoxycytidine) and interferons: antitumor activity and toxicity. Oncol Rep 1998; 5(6): 1555–1560. 19. Ryan CW, Vogelzang NJ, Stadler WM. A phase II trial of intravenous gemcitabine and 5-fluorouracil with subcutaneous interleukin-2 and interferon-alpha in patients with metastatic renal cell carcinoma. Cancer 2002; 94(10): 2602–2609. 20. Neri B, Doni L, Gemelli MT et al. Phase II trial of weekly intravenous gemcitabine administration with interferon and interleukin-2 immunotherapy for metastatic renal cell cancer. J Urol 2002; 168(3): 956–958. 21. Guida M, Lorusso V, De Lena M et al. Subcutaneous rIL-2 plus vinorelbine (VNB) and gemcitabine (GEM) in metastatic renal cell carcinoma. Annual Meeting of American Society of Clinical Oncology (ASCO) 2002. 22. Nanus DM, Garino A, Milowsky MI et al. Active chemotherapy for sarcomatoid and rapidly progressing renal cell carcinoma. Cancer 2004; 101(7): 1545–1551. 23. Porta C, Zimatore M, Imarisio I et al. Gemcitabine and oxaliplatin in the treatment of patients with immunotherapy-resistant advanced renal cell carcinoma: final results of a single-institution Phase II study. Cancer 2004; 100(10): 2132–2138. 24. Parmiani G, Pilla L, Castelli C, Rivoltini. Vaccination of patients with solid tumors. Ann Oncol 2003; 14(6): 817–824. 25. Whiteside TL, Odoux C. Dendritic cell biology and cancer therapy. Cancer Immunol Immunother 2004; 53(3): 240–248.
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9. Mc Dermott DF, Regan MM, Clark JI et al. Randomized phase III trial of high-dose interleukin-2 versus subcutaneous interluekin-2 and interferon in patients with metastatic renal cell carcinoma. J Clin Oncol 2005; 23: 133–141. 10. Fossa SD, Martinelli G, Otto U et al. Recombinant interferon alpha-2a with or without vinblastine in metastatic renal cell carcinoma: result of a European multicenter phase III study. Ann Oncol 1992; 3: 301–305. 11. Motzer RJ, Berg W, Ginsberg M et al. Phase II trial of thalidomide for patients with advanced renal cell carcinoma. J Clin Oncol 2002; 20(1): 302–306. 12. Atzpodien J, Kirchner H, Bergmann L et al. Interleukin-2 and interferon Alfa-2a-based immunochemotherapy in advanced renal cell carcinoma: a Prospectively Randomized Trial of the German Cooperative Renal Carcinoma Chemoimmunotherapy Group (DGCIN). J Clin Oncol 2004; 22: 1188–1194. 13. Guida M, Latorre A, Selvaggi FP et al. Subcutaneous rIL-2 plus alpha interferon and vinblastine in metastatic renal cell carcinoma: a phase II study. Int J Oncol 1996; 10: 487–491. 14. Rohde D, Hayn HK, Blatter J et al. The efficacy of 2#,2#-difluorodeoxycytidine (gemcitabine) combined with interferon in human renal cell carcinoma cell lines. Int J Oncol 1998; 12(6): 1361–1366. 15. Nowak AK, Robinson BW, Lake RA. Gemcitabine exerts a selective effect on the humoral immune response: implications for combination chemo-immunotherapy. Cancer Res 2002; 62: 2353–2358. 16. De Mulder PH, Weissbach L, Jakse G et al. Gemcitabine: a phase II study in patients with advanced renal cancer. Cancer Chemother Pharmacol 1996; 37(5): 491–495.
Annals of Oncology
Annals of Oncology 18 (Supplement 6): vi149–vi152, 2007 doi:10.1093/annonc/mdm245
Immunotherapy for metastatic renal cell carcinoma: is it a therapeutic option yet? M. Guida* & G. Colucci Oncology Department, National Oncology Institute, Bari, Italy
introduction
cytokines
The management of metastatic renal cell cancer (MRCC) constituted a therapeutic challenge and no standard therapy has been established until few years ago. As known, RCC is a chemoresistant neoplasm with antiblastic agents inducing objective response only in a minority of patients. Recently, some multitarget-oriented drugs have shown an impressive activity in MRCC with a high percentage of partial response (PR) and/or stable disease (SD) and with a significant impact on survival [1, 2]. As known, RCC is one of the most immunoresponsive of human malignancies. Thus, immunotherapy remains one of the most important therapeutic options for these patients. The value of immunotherapy is its curative potential in some patients and its capability to obtain very durable responses as demonstrated by long-term follow-up [3, 4].
Interleukin 2 (IL-2), with or without lymphokine-activated killer cells, has demonstrated an important antitumoral activity in RCC. As single agent, IL-2 has been evaluated in various dose and treatment schedules yielding a response rate of 10%–23% [5, 6]. As the initial i.v. use of this cytokine was associated with severe toxicity requiring even intensive care support, several studies were initiated to evaluate the efficacy of IL-2 given s.c. This IL-2 administration modality seems to provide therapeutic efficacy similar to that reported for i.v. IL-2 while drastically reducing treatment-related toxicity to the point of even permitting outpatient care and self-administration [7]. However, the response rate and duration seem to be longer with high-dose IL-2 with respect to low dose [8]. Some authors recently have also reported a better survival for high-dose IL-2 [9]. When IL-2 was used in association with interferon (IFN), the results were quite similar, while toxicity was significantly enhanced [9].
*Correspondence to: Dr M. Guida, via Amendola 209, 70122 Bari, Italy. Tel: +39 080 5555239; Fax: +39 080 5555239; E-mail: [email protected]
ª 2007 European Society for Medical Oncology
symposium article
Downloaded from http://annonc.oxfordjournals.org/ at East Tennessee State University on June 16, 2015
Until 1 year ago, immunotherapy was considered the standard treatment of metastatic renal cell carcinoma (MRCC) producing objective response of 10%–20% and an overall survival of 1 year. Recently, some multitarget-oriented drugs have shown an impressive activity in MRCC with a high percentage of partial response and/or stable disease with a significant impact on survival. Nevertheless, immunotherapy remains another important therapeutic option for these patients. The value of immunotherapy is its curative potential in some patients and its capability to obtain very durable responses as demonstrated by long-term follow-up. Interesting results seem obtained also when immunotherapy is used in combination with some chemotherapeutic agents. Gemcitabine demonstrated be a good drug to combine with immunotherapy because of its little detrimental effects on cellular immunity. In phase II studies, interesting results have been reported. We treated 41 patients with MRCC using a biweekly schedule including s.c. interleukin 2 (IL-2), gemcitabine and vinorelbine. The overall response was 40% and the median survival was 24 months. Treatment was well tolerated and easily manageable. Vaccines are another promising treatment of RCC intended to stimulate a specific antineoplastic response. Vaccines have been explored both in an adjuvant and in a metastatic setting. We started a pilot study with dendritic cells vaccine loaded with autologous tumor in MRCC. The treatment has resulted feasible, well tolerated and effective in a minority of patients. In the future, combination immunotherapy with multitarget-oriented drugs may be one way forward. Also advances in cellular therapies and new immunomodulatory molecules as monoclonal antibodies are producing new therapeutic options. Finally, the identification of a panel of prognostic factors could provide an important tool to guide the choice of treatment of patients with a different risk profile. Therefore, the increasing therapeutic options for RCC should be seen not as a competition among the different treatments but as an expanding armamentarium available for these patients. Key words: chemoimmunotherapy, metastatic renal cell carcinoma, vaccine
symposium article
Annals of Oncology
chemoimmunotherapy Preclinical studies showed synergic-additive effects when immunotherapy is used in combination with some chemotherapeutic agents. Initially, improved results were reported with an association of chemotherapy plus IFN. However, randomized studies demonstrated only a small increase in overall response with no difference in survival [10, 11]. More recently, Atzpodien et al. [12] reported in a large randomized trial high percentage of responses (31%) and a very long survival (25 months) with the combination of s.c. IL-2 plus IFN-a and 5-flurouracil (5-FU) with respect to vinblastine and IFN-a. On the contrary, the addition of 13-cis-retinoic acid does not increase the results. Although encouraging, these results need further confirmatory studies. In our first experience with low-dose s.c. IL-2, IFN-a and vinblastine, we reported in 23 patients with MRCC 21.6% of overall response and a 65% of SD. The median overall survival was 11months, with 27 months for responders, 11 months for patients with SD and 8 months for patients with rapid progression [13].
experiences with gemcitabine plus immunotherapy Preclinical data showed that gemcitabine (GEM) could be a good drug to combine with immunotherapy. In fact, it has been demonstrated that IFN-a increases the cytotoxicity of GEM and the tumor responses of human RCC in xenografts [14]. Moreover, GEM seems to exert a selective detrimental effect on the humoral immune response but not on specific antitumor cellular immunity. It has also been reported that weekly short infusions of GEM are not associated with reduction of CD4/CD8 ratio and natural killer cell in patients with solid tumors [15]. In Table 1 are reported the principal experiences with GEM used without and in association with immunotherapy in MRCC. The efficacy of GEM alone [16] in chemotherapy-naive Table 1. Principal studies with gemcitabine in metastatic renal cell carcinoma Authors De Mulder et al. [16] Rini et al. [17] Rohde et al. [18]
No. of patients 39 39* 9**
Ryan et al. [19]
41
Neri et al. [20]
15
Guida et al. [21]
45
Treatment 2
GEM 800 mg/m , g 1, 8, 15 GEM 600 mg/m2, g 1, 8, 15 5-FU c.i. 150 mg/m2/days 1–21 GEM IFN-c GEM 5-FU c.i. IL-2 s.c. + IFN-a GEM IL-2 s.c. + IFN-a GEM Navelbine IL-2 s.c. + IFN-a
OR/CR (%)
TtP/OS (months)
8.1/2.5 17/O
OS 12.3 TtP 7
15/0
OS 13.5
14.6
6.6/20.6
28
14/20
40/6.6
OS 24
CR, complete response; TtP, time to progression; OR, overall response; OS, overall survival; GEM, gemcitabine; 5-FU, 5-fluorouracil; IL-2, interleukin 2; c.i., continuous infusion; IFN, interferon.
vi150 | Guida & Colucci
Volume 18 | Supplement 6 | June 2007
Downloaded from http://annonc.oxfordjournals.org/ at East Tennessee State University on June 16, 2015
MRCC has been explored in a phase II study and a response rate of 8% has been reported with a survival >12 months. Better results have been obtained when GEM was associated with other chemotherapeutic agents [17, 22, 23]. The association of GEM plus immunotherapy has been minimally explored. Rohde et al. [18] reported the results on nine patients pretreated with immunotherapy using GEM and IFN-c. The response was 15% and the overall survival was 13.5 months. Ryan et al. [19] in 41 patients, treated with GEM plus 5-FU continuous infusion, IFN-a and low dose of IL-2 given s.c., reported an overall response of 14.6% and an overall survival of 20.6 months. Neri et al. [20] using GEM in association with s.c. IL-2 and IFN-a in 15 untreated patients reported an overall response of 28%, with a time to progression and survival lasting 14 and 20 months, respectively. We explored the efficacy and tolerability of a schedule including low-dose s.c. IL-2 in association with GEM and vinorelbine (VRB) in a phase II trial using a biweekly schedule in patients with MRCC [21]. Forty-five patients were included in the study. The following schedule was used: IL-2 at 4.5 million IU daily from day 1 to day 4; GEM 1200 mg/m2 on day 1 and VRB 25 mg/m2 on day 1. Therapy was recycled every 14 days. The overall response was 40% with three patients (6.6%) obtaining a complete response (CR) and 15 (33.3%) PR; 13 (29%) experienced a SD and 14 (31%) progressed. Response occurred not only in soft tissue/lymph nodes (35%) and lung/pleural (30%) disease but also in bone/visceral (35%) disease. Median response duration was 20 months, 34+ for CR and 24 for PR. Median survival was 24 months, 27 for CR/PR/SD and 8 for progressive patients. Treatment was well tolerated and easily manageable. IL-2 was mainly administered as outpatient care. Most relevant toxicity was chemotherapy related with grade 1–2 neutropenia being most common. IL-2-related toxicity was as expected and completely reversible with stopping therapy. In summary, we demonstrated that biweekly GEM–VRB plus low-dose IL-2 is a feasible and effective regimen in MRCC with a good toxic profile. On the basis of the present
Annals of Oncology
data, we are carrying out a large phase III trial comparing this schedule versus IL-2 immunotherapy alone.
vaccinetherapy
Volume 18 | Supplement 6 | June 2007
administered i.d. at a dose of 10 · 106 cells every 2 weeks for four times, followed by monthly administration in responding/SD patients until progression or vaccine availability. Low-dose IL-2 was also administered for 4 days after each vaccination. Until now, 17 patients have been treated (12 melanoma and 5 RCC). It was possible to prepare vaccine for all patients. The procedure, even though feasible, was elaborate and expensive. Compliance and tolerability were very high. No side-effects were registered, except IL-2-related side-effects. With regard to efficacy, we observed two PR (one MM and one MRCC; duration 12 and 3+ months, respectively), six SD (OS 8–4 months), one no evidence of disease for 14 months (MM with hepatic disease removed surgically), six PD and two not valuable (early). Although significant progress has been made in vaccine therapy, is still a long way to go.
conclusions RCC is one of the most immunoresponsive of human malignancies; thus, immunotherapy remains one of the most important therapeutic options for this neoplasm. Moreover, despite exciting results obtained with the advent of the new tyrosine kinase inhibitors, the value of immunotherapy is its curative potential in some patients and its capability to obtain very durable responses. Combination immunotherapy with multitarget-oriented drugs may be one way forward. Also the identification of a panel of prognostic factors could provide an important tool to guide the choice of treatment of patients with a different risk profile. Moreover, advances in cellular therapies, vaccines and new immunomodulatory molecules as monoclonal antibodies are producing new therapeutic options. Thus, the increasing choices available at present should be considered not as a competition among the different treatments but as an expanding armamentarium for the patients with MRCC.
references 1. Motzer RJ, Hutson TE, Tomczak P et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007; 356: 115–124. 2. Escudier B, Eisen T, Stadler WM et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007; 356: 125–134. 3. Yang JC, Childs R. Immunotherapy for renal cell cancer. J Clin Oncol 2006; 24: 5576–5583. 4. Parton M, Gore M, Eisen T. Role of cytokine therapy in 2006 and beyond for metastatic renal cell carcinoma. J Clin Oncol 2006; 24: 5584–5592. 5. 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 1987; 316: 889–897. 6. Dilman RO, Church D, Oldham RK et al. Inpatient continuous-infusion of interleukin-2 in 788 patients with cancer. The National Biotherapy Study Group experience. Cancer 1993; 71: 2358–2370. 7. Atzpodien MJ, Korfen A, Franks CR et al. Home therapy with recombinant interleukin-2 and interferon-2b in advanced human malignancies. Lancet 1990; 335: 1509–1512. 8. Yang JC, Sherry RM, Steinberg SM et al. Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer. J Clin Oncol 2003; 21(16): 3127–3132.
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Vaccines are a promising but still experimental treatment of RCC. This approach theoretically should permit the selective and safe destruction of the neoplastic cells because they are intended to stimulate a specific tumor-protective immune response against neoplastic cells that share some antigens contained in the administered vaccine [3, 24, 25]. Vaccines can stimulate both antibody and cellular response against tumor. The type of response induced, its frequency and its magnitude depend on vaccine construct and on the adjuvant used. Cancer vaccines can be grouped in cellular, anti-idiotype, peptide/protein based, glycolipid, and nucleic acid based. Immunological adjuvants can include not only the more classical ones (incomplete Freund’s adjuvant, alum, bacille Calmette–Guerin, QS-21) but also new molecules as cytokines [IL-2, IL-12 and granulocyte–macrophage colony-stimulating factor (GM-CSF)] or high purified immunogenic proteins cocktail (heat shock proteins) or dendritic cells (DCs). To date, it is unclear what is the best number of antigens required to induce a more effective and clinically relevant immune response. For these reasons, several authors prefer to use vaccines containing a broad array of antigens rather than single, highly purified antigen. The stimulation of immune response against multiple targets should increase the chances of killing neoplastic cells and minimize the chances that tumor cells will be able to down-modulate the expression of all the targeted antigens to avoid immune attack [24]. Clinical trials are shown that vaccines are safe to use and have much less toxicity than other current therapies. Moreover, a growing body of evidence indicates that vaccines can be clinically effective although in a minority of patients. The recent use of DCs loaded ex vivo with a wide variety of tumor antigens has increased the frequency of tumor-specific immune responses and clinical regressions [25]. Though clinical trials conducted so far remains unsatisfactory, numerous new findings and knowledge in basic immunology and molecular biology indicate that these results could be significantly improved in the next future [24]. In RCC, vaccine has been explored both in an adjuvant and in a metastatic setting. A randomized phase III trial using an autologous tumor cell vaccine versus no treatment has showed a significant advantage for patients treated versus the control arm in terms of both disease-free and overall survival [25]. Another large phase III trial using heat shock protein versus observation in patients with high-risk recurrence after surgical treatment is ongoing. In MRCC, several experiences have been made using different types of vaccine (neoplastic cell, heat shock protein, DC) with an overall response resulting in 10% [3]. We started a pilot study with DC generated from peripheral blood mononuclear cells obtained from leukapheresis procedure. After 6 days culture with IL-4 and GM-CSF, DCs were pulsed with autologous tumor lysate and matured with a cocktail of cytokines. Vaccine was
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17. Rini BI, Vogelzang NJ, Dumas MC et al. Phase II trial of weekly intravenous gemcitabine with continuous infusion fluorouracil in patients with metastatic renal cell cancer. J Clin Oncol 2000; 18(12): 2419–2426. 18. Rohde D, Thiemann D, Wildberger J et al. Treatment of renal cancer patients with gemcitabine (2#,2#-difluorodeoxycytidine) and interferons: antitumor activity and toxicity. Oncol Rep 1998; 5(6): 1555–1560. 19. Ryan CW, Vogelzang NJ, Stadler WM. A phase II trial of intravenous gemcitabine and 5-fluorouracil with subcutaneous interleukin-2 and interferon-alpha in patients with metastatic renal cell carcinoma. Cancer 2002; 94(10): 2602–2609. 20. Neri B, Doni L, Gemelli MT et al. Phase II trial of weekly intravenous gemcitabine administration with interferon and interleukin-2 immunotherapy for metastatic renal cell cancer. J Urol 2002; 168(3): 956–958. 21. Guida M, Lorusso V, De Lena M et al. Subcutaneous rIL-2 plus vinorelbine (VNB) and gemcitabine (GEM) in metastatic renal cell carcinoma. Annual Meeting of American Society of Clinical Oncology (ASCO) 2002. 22. Nanus DM, Garino A, Milowsky MI et al. Active chemotherapy for sarcomatoid and rapidly progressing renal cell carcinoma. Cancer 2004; 101(7): 1545–1551. 23. Porta C, Zimatore M, Imarisio I et al. Gemcitabine and oxaliplatin in the treatment of patients with immunotherapy-resistant advanced renal cell carcinoma: final results of a single-institution Phase II study. Cancer 2004; 100(10): 2132–2138. 24. Parmiani G, Pilla L, Castelli C, Rivoltini. Vaccination of patients with solid tumors. Ann Oncol 2003; 14(6): 817–824. 25. Whiteside TL, Odoux C. Dendritic cell biology and cancer therapy. Cancer Immunol Immunother 2004; 53(3): 240–248.
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9. Mc Dermott DF, Regan MM, Clark JI et al. Randomized phase III trial of high-dose interleukin-2 versus subcutaneous interluekin-2 and interferon in patients with metastatic renal cell carcinoma. J Clin Oncol 2005; 23: 133–141. 10. Fossa SD, Martinelli G, Otto U et al. Recombinant interferon alpha-2a with or without vinblastine in metastatic renal cell carcinoma: result of a European multicenter phase III study. Ann Oncol 1992; 3: 301–305. 11. Motzer RJ, Berg W, Ginsberg M et al. Phase II trial of thalidomide for patients with advanced renal cell carcinoma. J Clin Oncol 2002; 20(1): 302–306. 12. Atzpodien J, Kirchner H, Bergmann L et al. Interleukin-2 and interferon Alfa-2a-based immunochemotherapy in advanced renal cell carcinoma: a Prospectively Randomized Trial of the German Cooperative Renal Carcinoma Chemoimmunotherapy Group (DGCIN). J Clin Oncol 2004; 22: 1188–1194. 13. Guida M, Latorre A, Selvaggi FP et al. Subcutaneous rIL-2 plus alpha interferon and vinblastine in metastatic renal cell carcinoma: a phase II study. Int J Oncol 1996; 10: 487–491. 14. Rohde D, Hayn HK, Blatter J et al. The efficacy of 2#,2#-difluorodeoxycytidine (gemcitabine) combined with interferon in human renal cell carcinoma cell lines. Int J Oncol 1998; 12(6): 1361–1366. 15. Nowak AK, Robinson BW, Lake RA. Gemcitabine exerts a selective effect on the humoral immune response: implications for combination chemo-immunotherapy. Cancer Res 2002; 62: 2353–2358. 16. De Mulder PH, Weissbach L, Jakse G et al. Gemcitabine: a phase II study in patients with advanced renal cancer. Cancer Chemother Pharmacol 1996; 37(5): 491–495.
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