Engineered antibodies act as targeted therapies in cancer treatment
http://www.100md.com
《美国医学杂志》
Albert Einstein College of Medicine Cancer Center, Bronx,New York, USA
Abstract
Over the last two decades cancer cure rates have not gone up as expected, and the effectiveness of chemotherapy has reached a plateau. This has prompted a search for targeted therapies with higher efficacy and lesser toxicities. Monoclonal antibodies against cancer cells offer targeted therapies with little or no toxicities against normal tissues. In this review we will discuss the concepts behind the development of monoclonal antibodies in cancer and their present status in the clinic. Specifically, we will discuss the clinical use of Rituximab (Rituxanó), Trastuzumab (Herceptinó) and Bevacizumab (Avastinó) in various cancers and the key clinical trials that have led to their incorporation in cancer therapeutics.
Keywords: Cancer cure; Chemotherapy; Monoclonal antibodies
Since the discovery of antibodies nearly a century ago, scientists have explored ways to use them in therapy. Polyclonal antibodies against viruses and other infectious diseases were the first antibody therapies to be used clinically. A major milestone in this field was the discovery of methods to produce monoclonal antibodies on a large scale. Even then, the high rate of rejection of these murine antibodies by the human immune system was a constant barrier to their use in humans. Recent advancements in molecular biology have allowed the construction of chimeric antibodies with both human and mice elements Figure1. These humanized chimeric antibodies have a mouse-derived variable antigen-specific region fused to a heavy chain derived from humans and so do not elicit a major immune response from the host. In the last 5 years, the promise of antibody based therapy is finally being realized in the field of oncology. With conventional chemotherapy reaching a plateau in its effectiveness, antibody based therapies are showing a new hope to many patients. The development of antibodies was based on the premise that unlike chemotherapy which affects all diving cells, antibodies would bind with high specificity to specific cell surface antigens, resulting in targeted killing of malignant cells and relative sparing of normal cells. It is finally now, that we are seeing these concepts come into clinic practice and Ehrlich's description of antibodies as "the magic bullet" are finally being realized.
Rituximab
Rituximab (Rituxanó, Genetech) was the first monoclonal antibody approved by the Food and Drug Administration (FDA) for the treatment of cancer in 1997 and has become a successful drug in the last 5 years. This monoclonal antibody is directed against the CD-20 antigen which is present on the surface of 95% of Non Hodgkins lymphoma (NHL) cells.[1] The CD20 antigen is also present on the surface of normal B cells and other cancerous cells such as indolent lymphomas and some cases of acute lymphoblastic leukemia (ALL). Even though it is present on the surface of malignant lymphocytes in chronic lymphocytic leukemia (CLL) and malignant plasma cells in multiple myeloma, the expression is dim and much less than NHL.[2]
Rituxumab is a chimeric antibody where the murine anti-human CD20 portion is fused with human IgG1 heavy chain and kappa light chain region. The chimeric nature of the antibody leads to less human against mouse antibody (HAMA) production. More importantly, the human Fc portion of the antibody is needed to activate complement and activate antibody dependant cellular toxicity (ADCC) against the cancer cells. Thus the binding of rituximab to cells expressing CD20 triggers cell death directly by causing apoptosis and also by stimulating an immune reaction against the cell by ADCC and complement dependant mechanisms. This results in selective killing of the malignant CD20+ cells and normal B cells expressing CD20 without toxicity to any other cell lines.[2]
Multiple studies have shown the utility of Rituximab in lymphomas. Combination of chemotherapy (CHOP) and rituxumab (R) is now the standard of care in cases of diffuse large B cell lymphomas after a seminal trial showed that CHOP+R combination led to better overall survival when compared to CHOP alone. (70% vs 57%).[3] Since then, there have been multiple other studies showing higher cure rates with combination of Chemotherapy with Rituximab in aggressive NHLs.[4]
The utility of Rituximab has also been demonstrated in indolent lymphomas. As opposed to aggressive lymphomas, indolent lymphomas are much harder to cure with chemotherapy alone, and bone marrow transplantation is the only curative option at present. The addition of Rituximab has improved the cure rates. It has been tested as a single agent and in combination with various chemotherapy regimens such as CHOP[5] and FND[6] as first line therapy for indolent lymphomas. It has demonstrated impressive remission rates. Subsequent trials have also evaluated whether Rituximab can be given as maintenance therapy in lymphomas after a clinical remission is achieved after treatment with chemotherapy. These maintenance strategies led to longer duration of remission in these patients and also led to a 43% decrease in the risk of progression of the lymphoma.[5]
Mantle cell lymphoma is a subtype of NHL which carries a very poor prognosis. This subtype of lymphoma is very hard to cure with conventional chemotherapy and tends to involve extranodal sites. As majority of mantle cell lymphomas express CD20, Rituximab has been tried in combination with chemotherapy and has shown to improve disease free and overall survival which is comparable to results achieved after transplantation.[1]
Due to its remarkable efficacy in killing contaminating lymphoma cells, Rituximab is also being used to purify stem cells grafts used in bone marrow transplants. This process is known as purging and is usually accomplished by administration of Rituximab before the collection of stem cells is initiated. These transplants have been shown to be associated with lower rates of relapse of the lymphoma.[7]
In addition to its utility in malignant disorders, Rituximab has also shown utility in autoimmune disorders due to its activity against normal B cells. It has been shown to be therapeutic in refractory cases of Immune thrombocytopenic purpura, autoimmune hemolytic anemias and even cases of rheumatoid arthritis and SLE.[8] Clearly Rituximab has been a revolutionary advance in the treatment of B cell malignancies.
Zevalin and Bexxar
After the success of Rituximab, it was realized that the CD20 antigen is a good therapeutic target in a variety of lymphomas and lymphoid malignancies. Since Rituximab relies a lot on the immune system to kill the malignant cells, it was thought that conjugating it with radioactive particle may augment its efficacy. It was also hypothesized that in addition to killing cells that express the CD20 antigen, the radiation component of this radiolabeled-antibody would target bystander malignant cells that do not express CD20.
Zevalinó (Y90 Ibritumomab, Biogen Idec)
It was the first radioimmuno-agent to be approved by the FDA. This is the combination of CD20 antibody with radioactive Yttrium. The utility of this agent was demonstrated in a trial in patients with chemotherapy refractory lymphoma who were given Zevalin and Rituxumab. The overall response rate seen with Zevalin was higher than with Rituximab ( 80% vs 56%).[9] The importance of the radioactive (Y90) part of Zevalin has also been shown by a trial which evaluated the efficacy of this agent in patients with Rituximab refractory lymphomas. The overall response rate in these patients was 74%.[10] This is now being evaluated in many trials for a variety of lymphomas.
Bexxar ( I131 Tositumomab)
It was approved by the FDA in 2003 for patients with CD20+ lymphomas that were refractory to Rituximab. It has been shown to be effective in patients with relapsed lymphomas that are refractory to chemotherapy and has been shown to lead to responses in approximately 65% of patients.[11]
As opposed to Rituximab which causes no myelosuppresion, both of these radioimmunoconjugates do cause bone marrow suppression due to the radiation. This is reversible with a nadir around 5-6 weeks after treatment. For this reason, patients with more than 25% involvement of the marrow by the lymphoma are not treated with these due to the risk of very severe marrow suppression.
Herceptin
The human epidermal growth factor her-2-neu is found to be overexpressed in 15-20% of breast cancers. Tumors that overexpress her-2-neu are more aggressive and carry a poor prognosis. The work of Dennis Slamon in collaboration with scientists from Genentech led to the development of a murine antibody against this receptor, which was subsequently humanized for clinical use. This antibody Herceptinó (Trastuzumab, Genetech) is 95% human and 5% mouse and is used in the clinic.
Initial trials with Herceptin were done in previously treated patients who had relapsed with metastatic breast cancer. Even though the response rate was around 11%, Herceptin led to stabilization of the tumors in many cases, raising the possibility that it had activity against breast cancer.
Subsequent in vitro studies combined various chemotherapeutic regimens with Herceptin and observed synergistic cell killing with drugs such as adriamycin, cisplatin and taxanes. This led to an important clinical trial in women with metastatic breast cancers (with overexpression of her-2-neu when tested higher than 2+ by immunohistochemistry) who were given either adriamycin or taxol based chemotherapy with or without Herceptin. Slamon and collegues observed that patients who received Herceptin had a better survival 29 vs 20 months) and better duration of response (10 vs 5.6 mo). Interestingly, the combination of anthracycline adriamycin and Herceptin led to increased cardiotoxicity and congestive heart failure in this trial (26%). Thus it is not recommended that anthracyclines and Herceptin should be combined.[12]
The results of this study led to the approval of Herceptin for the treatment of breast cancers that overexpress her-2-nue. In addition to Immunohistochemistry, breast tumors are now tested for her-2-neu gene overexpression by FISH, which seems to be a better predictor of response to Herceptin if more than one copies of the gene are found. Presently, multiple trials are underway evaluating Herceptin in adjuvant therapy for resected tumors and as maintenance therapy as a single agent.
Campathó (Alemtuzumab, Ilex Pharmaceuticals)
It is a chimeric humanized antibody against the CD52 antigen which is present on the surface of all mature lymphocytes and monocytes. Since this antigen is found on the surface of most lymphoid malignancies Campath has been tried in the treatment of chronic lymphocytic leukemia (CLL) and lymphomas.
The first use of Campath was in relapsed cases of CLL where Campath led to a 33% response rate a single agent.[13] This study led to its approval by the FDA for use in CLL. It was subsequently tested in many trials and showed response rates between 33% to 57%.[14] Evidence of this activity led to its use as first line therapy in untreated CLL where it showed impressive activity (89% response with 33% rate of complete remission).[14] Even though Campath use led to rapid clearance of blood and bone marrow disease, it did not have great efficacy for bulky nodal disease. In addition to killing malignant lymphocytes, Campath was also seen to lead to rapid clearance of normal lymphocytes and led to decreased lymphocyte counts for prolonged periods. This led to high rates of infections in these patients with 16% to 33% recurrence of CMV and other infections such as varicella and Pneumocytis Carynii pneumonia.[15]
After the success in CLL, it has been tried in many different lymphomas. It was seen that it was also active in indolent follicular lymphomas and Waldenstrom's macroglobunemia.
Campath has also been used in combination with Rituximab in refractory cases of CLL. This combination led to a 63% response rate in patients with CLL that were refractory to conventional chemotherapy.[16] These combinations are now being tried in larger clinical trials. Initially, Campath was tested as an intravenous agent. Now the most popular method of administration is subcutaneous as it does not lead to severe infusion toxicities and reactions.
Due to its impressive anti-lymphocyte activity, Campath is also being used pretransplant to reduce the numbers of lymphocytes in stem cell grafts used in bone marrow transplants. This strategy leads to less Graft vs Host disease after transplantation. Initial trials look encouraging.
Combotox (CD19, CD22 Immunotoxin)
To increase the efficacy of antibodies against cancers, efforts have been made to conjugate them with poisons (Immunotoxins). The CD19 and CD22 antigens that are present on the surface of most cases of childhood and adult Acute Lymphoblastic Leukemia (ALL) can be targeted in the treatment of relapsed and refractory cases of this leukemia. As opposed to CD20, these antigens are internalized after antibody binding and thus offer attractive therapeutic targets for antibodies bound to poisons. An antibody developed on this strategy is Combotox, a 1:1 mixture of CD19 and CD22 antibodies bound to ricin. Ricin is an intracellular poison that interferes with RNA transcription and leads to cell death. Thus the combotox immunotoxin would selectively target CD19 and CD22 positive leukemic cells and result in their death. This Immunotoxin has been shown to be active in mouse models of lymphoid leukemias[17] Results of an ongoing trial in children with refractory and relapsed cases of ALL appear promising. We are currently conducting a trial, evaluating this compound in cases of refractory ALL in adults.
Avastin (Bevacizumab, Genetech)
Avastinó is the newest monoclonal antibody to be approved by the FDA. This antibody targets the receptor for the Vascular Endothelial Growth factor (VEGF). This factor is secreted by tumors and stimulates new blood vessel formation around the tumor and helps in the growth of the tumor. This process is called Angiogenesis and thus Avastin belongs to a new class of cancer therapies known as anti-angiogenic agents.
VEGF has been found to be over expressed in many tumors including kidney and colorectal cancers. This led to trials of Avastin in these two malignancies. In a landmark trial in colorectal cancer, 923 patients with metastatic colon cancers were randomized to either chemotherapy alone or chemotherapy in combination with Avastin. Patients that received Avastin had a 30% better survival than those with chemotherapy alone. This is the first ever trial in colon cancer to show such a dramatic difference between two competing treatments and led to FDA approval for Avastin in advanced colon cancer.
Avastin has also been tested in metastatic renal cell cancer and has been shown to slow down the progression of this cancer.[18] Renal cell cancer is presently an irremediable cancer with very poor rates of cure with chemotherapy. This is a very vascular tumor and has been associated with high levels of VEGF. It is hoped that future trials with Avastin may offer some hope for patients with advanced renal cell carcinoma.
Recently, Avastin was also tested in metastatic lung cancer in combination with chemotherapy. 887 patients were randomized to either receive a combination of Taxol, Carboplatinum chemotherapy and Avastin or chemotherapy alone. The group that recieved Avastin showed a better response rate (27% vs 10%, p<0.0001), progression-free survival (6.4 mo vs 4.5 mo, p<0.0001), and median survival (12.5 mo vs 10.2 mo, p=0.0075).[19] This landmark study is leading to the incorporation of Avastin in many lung cancer treatment regimens.
Since Avastin targets new blood vessel formation, it has been associated with poor wound healing and some cases of gastrointestinal bleeding. The most common side effects seen in trials have been hypertension and some cases of nephrotic syndrome.
Conclusion
Monoclonal antibodies have certainly improved cure rates in various cancers and have demonstrated the success of targeted therapies in oncology. In addition to the antibodies we have discussed, many more are in development. Advances in genomics and proteomics are leading to the discovery of many new tumor specific antigens that can be targeted by antibodies. It is hoped that future therapies may consist of a combination of various antibodies targeting different antigens on the cancer cell. These tailor made custom therapies may also combine chemotherapy and various kinase inhibitors in an attempt to improve cure rates, while decreasing side effects for individual cancer patients.
References
1. Avivi I, Robinson S, Goldstone A. Clinical use of rituximab in haematological malignancies. Br J Cancer 2003; 89: 1389-1394.
2. Smith MR. Rituximab (monoclonal anti-CD20 antibody): Mechanisms of action and resistance. Oncogene 2003; 22: 7359-7368.
3. Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R, Morel P, Van Den Neste E, Salles G, Gaulard P, Reyes F, Lederlin P, Gisselbrecht C. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 2002; 346: 235-242.
4. Vose JM, Link BK, Grossbard ML, Czuczman M, Grillo-Lopez A, Gilman P, Lowe A, Kunkel LA, Fisher RI. Phase II study of rituximab in combination with chop chemotherapy in patients with previously untreated, aggressive non-Hodgkin's lymphoma. J Clin Oncol 2001; 19: 389-397.
5. Hainsworth JD, Litchy S, Barton JH, Houston GA, Hermann RC, Bradof JE, Greco FA. Single-agent rituximab as first-line and maintenance treatment for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma: A phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol 2003; 21: 1746-1751.
6. McLaughlin P, Hagemeister FB, Rodriguez MA, Sarris AH, Pate O, Younes A, Lee MS, Dang NH, Romaguera JE, Preti AH, McAda N, Cabanillas F. Safety of fludarabine, mitoxantrone, and dexamethasone combined with rituximab in the treatment of stage IV indolent lymphoma. Semin Oncol 2000; 27: 37-41.
7. Horwitz SM, Negrin RS, Blume KG, Breslin S, Stuart MJ, Stockerl-Goldstein KE, Johnston LJ, Wong RM, Shizuru JA, Horning SJ. Rituximab as adjuvant to high-dose therapy and autologous hematopoietic cell transplantation for aggressive non-Hodgkin lymphoma. Blood 2004; 103: 777-783.
8. Kazkaz H, Isenberg D. Anti B cell therapy (rituximab) in the treatment of autoimmune diseases. Curr Opin Pharmacol 2004; 4: 398-402.
9. Witzig TE, White CA, Gordon LI, Wiseman GA, Emmanouilides C, Murray JL, Lister J, Multani PS. Safety of yttrium-90 ibritumomab tiuxetan radioimmunotherapy for relapsed low-grade, follicular, or transformed non-hodgkin's lymphoma. J Clin Oncol 2003; 21: 1263-1270.
10. Witzig TE, Gordon LI, Cabanillas F, Czuczman MS, Emmanouilides C, Joyce R, Pohlman BL, Bartlett NL, Wiseman GA, Padre N, Grillo-Lopez AJ, Multani P, White CA. Randomized controlled trial of yttrium-90-labeled ibritumomab tiuxetan radioimmunotherapy versus rituximab immunotherapy for patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma. J Clin Oncol 2002; 20: 2453-2463.
11. Kaminski MS, Zelenetz AD, Press OW, Saleh M, Leonard J, Fehrenbacher L, Lister TA, Stagg RJ, Tidmarsh GF, Kroll S, Wahl RL, Knox SJ, Vose JM. Pivotal study of iodine I 131 tositumomab for chemotherapy-refractory low-grade or transformed low-grade B-cell non-Hodgkin's lymphomas. J Clin Oncol 2001; 19: 3918-3928.
12. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001; 344: 783-792.
13. Keating MJ, Flinn I, Jain V, Binet JL, Hillmen P, Byrd J, Albitar M, Brettman L, Santabarbara P, Wacker B, Rai KR. Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: Results of a large international study. Blood 2002; 99: 3554-3561.
14. Osterborg A, Mellstedt H, Keating M. Clinical effects of alemtuzumab (Campath-1H) in B-cell chronic lymphocytic leukemia. Med Oncol 2002;19 Suppl: S21-26
15. Moreton P, Hillmen P. Alemtuzumab therapy in B-cell lymphoproliferative disorders. Semin Oncol 2003; 30: 493-501.
16. Faderl S, Thomas DA, O'Brien S, Garcia-Manero G, Kantarjian HM, Giles FJ, Koller C, Ferrajoli A, Verstovsek S, Pro B, Andreeff M, Beran M, Cortes J, Wierda W, Tran N, Keating MJ. Experience with alemtuzumab plus rituximab in patients with relapsed and refractory lymphoid malignancies. Blood 2003;101:3413-3415
17. Herrera L, Farah RA, Pellegrini VA, Aquino DB, Sandler ES, Buchanan GR, Vitetta ES. Immunotoxins against CD19 and CD22 are effective in killing precursor-B acute lymphoblastic leukemia cells in vitro. Leukemia 2000;14: 853-858.
18. Yang JC, Haworth L, Sherry RM, Hwu P, Schwartzentruber DJ, Topalian SL, Steinberg SM, Chen HX, Rosenberg SA. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 2003; 349: 427-434.
19. Sandler AB, Gray R, Brahmer J, Dowlati A, Schiller JH, Perry MC, Johnson DH. Randomized phase II/III Trial of paclitaxel (P) plus carboplatin (C) with or without bevacizumab (NSC # 704865) in patients with advanced non-squamous non-small cell lung cancer (NSCLC): An Eastern Cooperative Oncology Group (ECOG) Trial-E4599. J Clinical Oncology 2005; 23: LBA4.(Mohindru Mani, Verma Amit)
Abstract
Over the last two decades cancer cure rates have not gone up as expected, and the effectiveness of chemotherapy has reached a plateau. This has prompted a search for targeted therapies with higher efficacy and lesser toxicities. Monoclonal antibodies against cancer cells offer targeted therapies with little or no toxicities against normal tissues. In this review we will discuss the concepts behind the development of monoclonal antibodies in cancer and their present status in the clinic. Specifically, we will discuss the clinical use of Rituximab (Rituxanó), Trastuzumab (Herceptinó) and Bevacizumab (Avastinó) in various cancers and the key clinical trials that have led to their incorporation in cancer therapeutics.
Keywords: Cancer cure; Chemotherapy; Monoclonal antibodies
Since the discovery of antibodies nearly a century ago, scientists have explored ways to use them in therapy. Polyclonal antibodies against viruses and other infectious diseases were the first antibody therapies to be used clinically. A major milestone in this field was the discovery of methods to produce monoclonal antibodies on a large scale. Even then, the high rate of rejection of these murine antibodies by the human immune system was a constant barrier to their use in humans. Recent advancements in molecular biology have allowed the construction of chimeric antibodies with both human and mice elements Figure1. These humanized chimeric antibodies have a mouse-derived variable antigen-specific region fused to a heavy chain derived from humans and so do not elicit a major immune response from the host. In the last 5 years, the promise of antibody based therapy is finally being realized in the field of oncology. With conventional chemotherapy reaching a plateau in its effectiveness, antibody based therapies are showing a new hope to many patients. The development of antibodies was based on the premise that unlike chemotherapy which affects all diving cells, antibodies would bind with high specificity to specific cell surface antigens, resulting in targeted killing of malignant cells and relative sparing of normal cells. It is finally now, that we are seeing these concepts come into clinic practice and Ehrlich's description of antibodies as "the magic bullet" are finally being realized.
Rituximab
Rituximab (Rituxanó, Genetech) was the first monoclonal antibody approved by the Food and Drug Administration (FDA) for the treatment of cancer in 1997 and has become a successful drug in the last 5 years. This monoclonal antibody is directed against the CD-20 antigen which is present on the surface of 95% of Non Hodgkins lymphoma (NHL) cells.[1] The CD20 antigen is also present on the surface of normal B cells and other cancerous cells such as indolent lymphomas and some cases of acute lymphoblastic leukemia (ALL). Even though it is present on the surface of malignant lymphocytes in chronic lymphocytic leukemia (CLL) and malignant plasma cells in multiple myeloma, the expression is dim and much less than NHL.[2]
Rituxumab is a chimeric antibody where the murine anti-human CD20 portion is fused with human IgG1 heavy chain and kappa light chain region. The chimeric nature of the antibody leads to less human against mouse antibody (HAMA) production. More importantly, the human Fc portion of the antibody is needed to activate complement and activate antibody dependant cellular toxicity (ADCC) against the cancer cells. Thus the binding of rituximab to cells expressing CD20 triggers cell death directly by causing apoptosis and also by stimulating an immune reaction against the cell by ADCC and complement dependant mechanisms. This results in selective killing of the malignant CD20+ cells and normal B cells expressing CD20 without toxicity to any other cell lines.[2]
Multiple studies have shown the utility of Rituximab in lymphomas. Combination of chemotherapy (CHOP) and rituxumab (R) is now the standard of care in cases of diffuse large B cell lymphomas after a seminal trial showed that CHOP+R combination led to better overall survival when compared to CHOP alone. (70% vs 57%).[3] Since then, there have been multiple other studies showing higher cure rates with combination of Chemotherapy with Rituximab in aggressive NHLs.[4]
The utility of Rituximab has also been demonstrated in indolent lymphomas. As opposed to aggressive lymphomas, indolent lymphomas are much harder to cure with chemotherapy alone, and bone marrow transplantation is the only curative option at present. The addition of Rituximab has improved the cure rates. It has been tested as a single agent and in combination with various chemotherapy regimens such as CHOP[5] and FND[6] as first line therapy for indolent lymphomas. It has demonstrated impressive remission rates. Subsequent trials have also evaluated whether Rituximab can be given as maintenance therapy in lymphomas after a clinical remission is achieved after treatment with chemotherapy. These maintenance strategies led to longer duration of remission in these patients and also led to a 43% decrease in the risk of progression of the lymphoma.[5]
Mantle cell lymphoma is a subtype of NHL which carries a very poor prognosis. This subtype of lymphoma is very hard to cure with conventional chemotherapy and tends to involve extranodal sites. As majority of mantle cell lymphomas express CD20, Rituximab has been tried in combination with chemotherapy and has shown to improve disease free and overall survival which is comparable to results achieved after transplantation.[1]
Due to its remarkable efficacy in killing contaminating lymphoma cells, Rituximab is also being used to purify stem cells grafts used in bone marrow transplants. This process is known as purging and is usually accomplished by administration of Rituximab before the collection of stem cells is initiated. These transplants have been shown to be associated with lower rates of relapse of the lymphoma.[7]
In addition to its utility in malignant disorders, Rituximab has also shown utility in autoimmune disorders due to its activity against normal B cells. It has been shown to be therapeutic in refractory cases of Immune thrombocytopenic purpura, autoimmune hemolytic anemias and even cases of rheumatoid arthritis and SLE.[8] Clearly Rituximab has been a revolutionary advance in the treatment of B cell malignancies.
Zevalin and Bexxar
After the success of Rituximab, it was realized that the CD20 antigen is a good therapeutic target in a variety of lymphomas and lymphoid malignancies. Since Rituximab relies a lot on the immune system to kill the malignant cells, it was thought that conjugating it with radioactive particle may augment its efficacy. It was also hypothesized that in addition to killing cells that express the CD20 antigen, the radiation component of this radiolabeled-antibody would target bystander malignant cells that do not express CD20.
Zevalinó (Y90 Ibritumomab, Biogen Idec)
It was the first radioimmuno-agent to be approved by the FDA. This is the combination of CD20 antibody with radioactive Yttrium. The utility of this agent was demonstrated in a trial in patients with chemotherapy refractory lymphoma who were given Zevalin and Rituxumab. The overall response rate seen with Zevalin was higher than with Rituximab ( 80% vs 56%).[9] The importance of the radioactive (Y90) part of Zevalin has also been shown by a trial which evaluated the efficacy of this agent in patients with Rituximab refractory lymphomas. The overall response rate in these patients was 74%.[10] This is now being evaluated in many trials for a variety of lymphomas.
Bexxar ( I131 Tositumomab)
It was approved by the FDA in 2003 for patients with CD20+ lymphomas that were refractory to Rituximab. It has been shown to be effective in patients with relapsed lymphomas that are refractory to chemotherapy and has been shown to lead to responses in approximately 65% of patients.[11]
As opposed to Rituximab which causes no myelosuppresion, both of these radioimmunoconjugates do cause bone marrow suppression due to the radiation. This is reversible with a nadir around 5-6 weeks after treatment. For this reason, patients with more than 25% involvement of the marrow by the lymphoma are not treated with these due to the risk of very severe marrow suppression.
Herceptin
The human epidermal growth factor her-2-neu is found to be overexpressed in 15-20% of breast cancers. Tumors that overexpress her-2-neu are more aggressive and carry a poor prognosis. The work of Dennis Slamon in collaboration with scientists from Genentech led to the development of a murine antibody against this receptor, which was subsequently humanized for clinical use. This antibody Herceptinó (Trastuzumab, Genetech) is 95% human and 5% mouse and is used in the clinic.
Initial trials with Herceptin were done in previously treated patients who had relapsed with metastatic breast cancer. Even though the response rate was around 11%, Herceptin led to stabilization of the tumors in many cases, raising the possibility that it had activity against breast cancer.
Subsequent in vitro studies combined various chemotherapeutic regimens with Herceptin and observed synergistic cell killing with drugs such as adriamycin, cisplatin and taxanes. This led to an important clinical trial in women with metastatic breast cancers (with overexpression of her-2-neu when tested higher than 2+ by immunohistochemistry) who were given either adriamycin or taxol based chemotherapy with or without Herceptin. Slamon and collegues observed that patients who received Herceptin had a better survival 29 vs 20 months) and better duration of response (10 vs 5.6 mo). Interestingly, the combination of anthracycline adriamycin and Herceptin led to increased cardiotoxicity and congestive heart failure in this trial (26%). Thus it is not recommended that anthracyclines and Herceptin should be combined.[12]
The results of this study led to the approval of Herceptin for the treatment of breast cancers that overexpress her-2-nue. In addition to Immunohistochemistry, breast tumors are now tested for her-2-neu gene overexpression by FISH, which seems to be a better predictor of response to Herceptin if more than one copies of the gene are found. Presently, multiple trials are underway evaluating Herceptin in adjuvant therapy for resected tumors and as maintenance therapy as a single agent.
Campathó (Alemtuzumab, Ilex Pharmaceuticals)
It is a chimeric humanized antibody against the CD52 antigen which is present on the surface of all mature lymphocytes and monocytes. Since this antigen is found on the surface of most lymphoid malignancies Campath has been tried in the treatment of chronic lymphocytic leukemia (CLL) and lymphomas.
The first use of Campath was in relapsed cases of CLL where Campath led to a 33% response rate a single agent.[13] This study led to its approval by the FDA for use in CLL. It was subsequently tested in many trials and showed response rates between 33% to 57%.[14] Evidence of this activity led to its use as first line therapy in untreated CLL where it showed impressive activity (89% response with 33% rate of complete remission).[14] Even though Campath use led to rapid clearance of blood and bone marrow disease, it did not have great efficacy for bulky nodal disease. In addition to killing malignant lymphocytes, Campath was also seen to lead to rapid clearance of normal lymphocytes and led to decreased lymphocyte counts for prolonged periods. This led to high rates of infections in these patients with 16% to 33% recurrence of CMV and other infections such as varicella and Pneumocytis Carynii pneumonia.[15]
After the success in CLL, it has been tried in many different lymphomas. It was seen that it was also active in indolent follicular lymphomas and Waldenstrom's macroglobunemia.
Campath has also been used in combination with Rituximab in refractory cases of CLL. This combination led to a 63% response rate in patients with CLL that were refractory to conventional chemotherapy.[16] These combinations are now being tried in larger clinical trials. Initially, Campath was tested as an intravenous agent. Now the most popular method of administration is subcutaneous as it does not lead to severe infusion toxicities and reactions.
Due to its impressive anti-lymphocyte activity, Campath is also being used pretransplant to reduce the numbers of lymphocytes in stem cell grafts used in bone marrow transplants. This strategy leads to less Graft vs Host disease after transplantation. Initial trials look encouraging.
Combotox (CD19, CD22 Immunotoxin)
To increase the efficacy of antibodies against cancers, efforts have been made to conjugate them with poisons (Immunotoxins). The CD19 and CD22 antigens that are present on the surface of most cases of childhood and adult Acute Lymphoblastic Leukemia (ALL) can be targeted in the treatment of relapsed and refractory cases of this leukemia. As opposed to CD20, these antigens are internalized after antibody binding and thus offer attractive therapeutic targets for antibodies bound to poisons. An antibody developed on this strategy is Combotox, a 1:1 mixture of CD19 and CD22 antibodies bound to ricin. Ricin is an intracellular poison that interferes with RNA transcription and leads to cell death. Thus the combotox immunotoxin would selectively target CD19 and CD22 positive leukemic cells and result in their death. This Immunotoxin has been shown to be active in mouse models of lymphoid leukemias[17] Results of an ongoing trial in children with refractory and relapsed cases of ALL appear promising. We are currently conducting a trial, evaluating this compound in cases of refractory ALL in adults.
Avastin (Bevacizumab, Genetech)
Avastinó is the newest monoclonal antibody to be approved by the FDA. This antibody targets the receptor for the Vascular Endothelial Growth factor (VEGF). This factor is secreted by tumors and stimulates new blood vessel formation around the tumor and helps in the growth of the tumor. This process is called Angiogenesis and thus Avastin belongs to a new class of cancer therapies known as anti-angiogenic agents.
VEGF has been found to be over expressed in many tumors including kidney and colorectal cancers. This led to trials of Avastin in these two malignancies. In a landmark trial in colorectal cancer, 923 patients with metastatic colon cancers were randomized to either chemotherapy alone or chemotherapy in combination with Avastin. Patients that received Avastin had a 30% better survival than those with chemotherapy alone. This is the first ever trial in colon cancer to show such a dramatic difference between two competing treatments and led to FDA approval for Avastin in advanced colon cancer.
Avastin has also been tested in metastatic renal cell cancer and has been shown to slow down the progression of this cancer.[18] Renal cell cancer is presently an irremediable cancer with very poor rates of cure with chemotherapy. This is a very vascular tumor and has been associated with high levels of VEGF. It is hoped that future trials with Avastin may offer some hope for patients with advanced renal cell carcinoma.
Recently, Avastin was also tested in metastatic lung cancer in combination with chemotherapy. 887 patients were randomized to either receive a combination of Taxol, Carboplatinum chemotherapy and Avastin or chemotherapy alone. The group that recieved Avastin showed a better response rate (27% vs 10%, p<0.0001), progression-free survival (6.4 mo vs 4.5 mo, p<0.0001), and median survival (12.5 mo vs 10.2 mo, p=0.0075).[19] This landmark study is leading to the incorporation of Avastin in many lung cancer treatment regimens.
Since Avastin targets new blood vessel formation, it has been associated with poor wound healing and some cases of gastrointestinal bleeding. The most common side effects seen in trials have been hypertension and some cases of nephrotic syndrome.
Conclusion
Monoclonal antibodies have certainly improved cure rates in various cancers and have demonstrated the success of targeted therapies in oncology. In addition to the antibodies we have discussed, many more are in development. Advances in genomics and proteomics are leading to the discovery of many new tumor specific antigens that can be targeted by antibodies. It is hoped that future therapies may consist of a combination of various antibodies targeting different antigens on the cancer cell. These tailor made custom therapies may also combine chemotherapy and various kinase inhibitors in an attempt to improve cure rates, while decreasing side effects for individual cancer patients.
References
1. Avivi I, Robinson S, Goldstone A. Clinical use of rituximab in haematological malignancies. Br J Cancer 2003; 89: 1389-1394.
2. Smith MR. Rituximab (monoclonal anti-CD20 antibody): Mechanisms of action and resistance. Oncogene 2003; 22: 7359-7368.
3. Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R, Morel P, Van Den Neste E, Salles G, Gaulard P, Reyes F, Lederlin P, Gisselbrecht C. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 2002; 346: 235-242.
4. Vose JM, Link BK, Grossbard ML, Czuczman M, Grillo-Lopez A, Gilman P, Lowe A, Kunkel LA, Fisher RI. Phase II study of rituximab in combination with chop chemotherapy in patients with previously untreated, aggressive non-Hodgkin's lymphoma. J Clin Oncol 2001; 19: 389-397.
5. Hainsworth JD, Litchy S, Barton JH, Houston GA, Hermann RC, Bradof JE, Greco FA. Single-agent rituximab as first-line and maintenance treatment for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma: A phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol 2003; 21: 1746-1751.
6. McLaughlin P, Hagemeister FB, Rodriguez MA, Sarris AH, Pate O, Younes A, Lee MS, Dang NH, Romaguera JE, Preti AH, McAda N, Cabanillas F. Safety of fludarabine, mitoxantrone, and dexamethasone combined with rituximab in the treatment of stage IV indolent lymphoma. Semin Oncol 2000; 27: 37-41.
7. Horwitz SM, Negrin RS, Blume KG, Breslin S, Stuart MJ, Stockerl-Goldstein KE, Johnston LJ, Wong RM, Shizuru JA, Horning SJ. Rituximab as adjuvant to high-dose therapy and autologous hematopoietic cell transplantation for aggressive non-Hodgkin lymphoma. Blood 2004; 103: 777-783.
8. Kazkaz H, Isenberg D. Anti B cell therapy (rituximab) in the treatment of autoimmune diseases. Curr Opin Pharmacol 2004; 4: 398-402.
9. Witzig TE, White CA, Gordon LI, Wiseman GA, Emmanouilides C, Murray JL, Lister J, Multani PS. Safety of yttrium-90 ibritumomab tiuxetan radioimmunotherapy for relapsed low-grade, follicular, or transformed non-hodgkin's lymphoma. J Clin Oncol 2003; 21: 1263-1270.
10. Witzig TE, Gordon LI, Cabanillas F, Czuczman MS, Emmanouilides C, Joyce R, Pohlman BL, Bartlett NL, Wiseman GA, Padre N, Grillo-Lopez AJ, Multani P, White CA. Randomized controlled trial of yttrium-90-labeled ibritumomab tiuxetan radioimmunotherapy versus rituximab immunotherapy for patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma. J Clin Oncol 2002; 20: 2453-2463.
11. Kaminski MS, Zelenetz AD, Press OW, Saleh M, Leonard J, Fehrenbacher L, Lister TA, Stagg RJ, Tidmarsh GF, Kroll S, Wahl RL, Knox SJ, Vose JM. Pivotal study of iodine I 131 tositumomab for chemotherapy-refractory low-grade or transformed low-grade B-cell non-Hodgkin's lymphomas. J Clin Oncol 2001; 19: 3918-3928.
12. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001; 344: 783-792.
13. Keating MJ, Flinn I, Jain V, Binet JL, Hillmen P, Byrd J, Albitar M, Brettman L, Santabarbara P, Wacker B, Rai KR. Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: Results of a large international study. Blood 2002; 99: 3554-3561.
14. Osterborg A, Mellstedt H, Keating M. Clinical effects of alemtuzumab (Campath-1H) in B-cell chronic lymphocytic leukemia. Med Oncol 2002;19 Suppl: S21-26
15. Moreton P, Hillmen P. Alemtuzumab therapy in B-cell lymphoproliferative disorders. Semin Oncol 2003; 30: 493-501.
16. Faderl S, Thomas DA, O'Brien S, Garcia-Manero G, Kantarjian HM, Giles FJ, Koller C, Ferrajoli A, Verstovsek S, Pro B, Andreeff M, Beran M, Cortes J, Wierda W, Tran N, Keating MJ. Experience with alemtuzumab plus rituximab in patients with relapsed and refractory lymphoid malignancies. Blood 2003;101:3413-3415
17. Herrera L, Farah RA, Pellegrini VA, Aquino DB, Sandler ES, Buchanan GR, Vitetta ES. Immunotoxins against CD19 and CD22 are effective in killing precursor-B acute lymphoblastic leukemia cells in vitro. Leukemia 2000;14: 853-858.
18. Yang JC, Haworth L, Sherry RM, Hwu P, Schwartzentruber DJ, Topalian SL, Steinberg SM, Chen HX, Rosenberg SA. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 2003; 349: 427-434.
19. Sandler AB, Gray R, Brahmer J, Dowlati A, Schiller JH, Perry MC, Johnson DH. Randomized phase II/III Trial of paclitaxel (P) plus carboplatin (C) with or without bevacizumab (NSC # 704865) in patients with advanced non-squamous non-small cell lung cancer (NSCLC): An Eastern Cooperative Oncology Group (ECOG) Trial-E4599. J Clinical Oncology 2005; 23: LBA4.(Mohindru Mani, Verma Amit)