Biologic Response Modifiers: Principles of Biotherapy
Mohamad Cherry
Howard Ozer
Biotherapy is one of the newest waves of cancer treatment. It uses drugs aimed at the patient’s own immune system to help fight cancer throughout the body. Biotherapy is also called biological therapy or immunotherapy and the drugs used are called biologic response modifiers. Although cancer therapy has primarily encompassed surgery, radiotherapy, and chemotherapy, the emergence of biologic response modifiers has revolutionized treatment for malignant diseases. Interferons, interleukins, tumor necrosis factor (TNF), monoclonal antibodies (mAbs), and tumor vaccines are all different types of immunotherapy treatments and are promising.
The earliest evidence suggesting the existence of an immune response to tumors was found more than a century ago when Coley observed spontaneous regression of tumors in patients recovering from an acute infection and attempted to treat cancer patients with an extract called Coley toxin.1 Spontaneous regression has occasionally been observed in various malignancies, particularly melanoma and renal cell carcinoma (RCC).2,3 This observation led to early attempts to immunize the tumor-bearing host by administration of nonspecific immune adjuvants such as Bacillus Calmette-Guérin (BCG), Corynebacterium parvum, or levamisole, or by the administration of tumor cells or their extracts utilized as vaccines. By and large, this form of active immunotherapy has been unsuccessful in humans and hence has been abandoned.4 However, as the understanding of tumor immunology progressed, new types of immunomodulators in the form of cytokines were discovered. Cytokines are soluble proteins secreted by cells of the immune system, either lymphocytes or monocytes, which then exert their growth-regulatory action on other target cells. They are true hormones that bind to specific receptors and alter cellular activities.5
The two families of cytokines most extensively characterized and investigated are the interferons and the interleukins. Interferons, comprising three major species—α , β , and γ—were first discovered >30 years ago and were initially characterized by their antiviral properties.6,7 The other group of cytokines is termed interleukins, a group of naturally occurring proteins that mediate communication between cells. Interleukins regulate cell growth, differentiation, and motility. They are particularly important in stimulating immune responses, such as inflammation. They were first identified by the function they exhibited in in vitro assays and were named accordingly—for example, macrophage-activating factor or T-cell growth factor.8 Finally, the most revolutionary addition to the armamentarium of cancer biotherapy has been the development of mAbs and vaccine therapy (Table 7.1).9
INTERFERON
Interferons comprise a family of related glycoproteins that possess antiviral, antiproliferative, and immunomodulating properties. Three distinct categories of interferons exist: α , β , and γ . These interferons differ in their antigenic, biologic, and chemical properties, as well as their inducers and the cell source from which they are derived. The advent of recombinant DNA technology allowed the production of highly purified recombinant forms of all three subtypes of interferons in large quantities. Dose-limiting toxicities included hypotension and CNS toxicity, with the most pronounced acute toxicity being pyrexia with flulike symptoms. Tachyphylaxis to the constitutional symptoms of fever, fatigue, anorexia, and malaise was noted after 1 week of therapy.10 A summary of the role of α interferon in the therapy for certain malignancies is described in the subsequent text.
Chronic Myelogenous Leukemia
Chronic myelogenous leukemia (CML) is a hyperproliferative disorder of a pluripotential hematopoietic stem cell that follows a triphasic clinical course, with a chronic phase followed by an accelerated phase merging into a blast crisis. It is estimated that 95% of patients with CML demonstrate a molecular rearrangement of the Abelson oncogene that is identified as the t(9:22) translocation or Philadelphia chromosome. In vitro studies with interferon in CML cell lines have demonstrated direct antiproliferative activity as well as downregulation of oncogene expression for the abnormal p210 protein.11,12,13,14
The suggestion that interferon α could induce hematologic responses and karyotypic remissions prompted further studies to determine if it could impact survival, which had previously only been accomplished through stem cell transplant (SCT).11,12,15,16 When compared with standard chemotherapy consisting of hydroxyurea or busulfan in a randomized controlled trial conducted by the Italian Cooperative Study Group (ICSG) on CML, interferon α-2a monotherapy resulted in a significantly prolonged time to progression as well as survival, >72 months versus 45 months and 72 months versus 52 months, respectively.17 The increased overall survival (OS) among patients who underwent treatment with interferon was maintained as demonstrated by long-term follow-up of the cohort of patients studied by the ICSG.20 Interferon, therefore, proved to be the first agent to induce cytogenetic responses in patients with CML and to confer a potential survival advantage, although complete cytogenetic responses were seen in only a minority of patients.
Table 7-1 Summary of Biologic Response Modifier Indications and Common Dosing | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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On the basis of in vitro studies of the potential synergistic effect of cytarabine (Cytosar) with interferon, a randomized trial comparing the combination with interferon α-2b alone was undertaken.21 The trial was stopped early as combination therapy demonstrated a definitive survival advantage. Major cytogenetic responses were seen in 41% of patients receiving cytarabine with interferon, compared with 24% with interferon alone, a statistically significant difference. The equivalency of low-dose interferon, defined as 3 million international units (MIU) per m2 five times a week, and high-dose interferon, defined as 5 MIU per m2 daily, with regard to progression-free survival, hematologic response rates, and cytogenetic response rates in conjunction with a much lower toxicity provided increased treatment potential.22 Although the advent of imatinib, dasatinib, and nilotinib, inhibitors of the BCR-ABL tyrosine kinase (TKIs), supplanted interferon as first-line therapy with complete cytogenetic response rates up to 76% to 100%, interferon remains a useful tool in the treatment for CML, especially in pregnancy or when these TKIs are contraindicated.18,19,23
Hairy Cell Leukemia
Hairy cell leukemia (HCL) is a relatively rare lymphoproliferative disorder with a typical presentation of pancytopenia and a hypercellular marrow with hairy cells and splenomegaly.24 Until the advent of interferon, splenectomy was the cornerstone of therapy, with normalization of blood counts occurring in 40% to 60% of patients following surgery. Quesada et al. reported an overall response rate (ORR) close to 100% when interferon is used in HCL patients.25 Subsequently, several single- and multi-institutional phase II studies were conducted using recombinant interferon α (2a or 2b) in HCL and revealed similar efficacy between the two recombinant interferons.26,27,28,29,30 The optimal duration of therapy, ranging from 6 to 18 months was also evaluated in these trials, and 12 months of therapy in responding patients was recommended.31 Long-term follow-up of early trials confirmed that interferon induced a satisfactory response, but that interruption of therapy typically resulted in disease recurrence.32,33,34 Currently, the use of purine analogs including pentostatin and 2-chlorodeoxyadenosine is widely used as these agents are proven to result in higher complete response (CR) rates with more durable remissions than interferon.35,36
Renal Cell Carcinoma
Early clinical studies with human and recombinant α interferon indicated a small but definite response rate in metastatic RCC.37,38 Previously, several randomized trials in which a 15% objective response rate and a small survival benefit were seen established interferon as a standard of care for initial therapy of patients with metastatic renal cell cancer.39,40,41 The lack of durable response was confirmed in long-term follow-up.42 Vascular endothelial growth factor (VEGF), a proangiogenic protein that produces increased vascular permeability and endothelial cell proliferation, has been demonstrated in most renal cell cancers and is significantly upregulated when compared with surrounding normal renal tissue.44,45 Two large randomized phase III trials (AVOREN43 and CALGB 90206)47 compared the combination of bevacizumab, an anti-VEGF mAb and interferon α to interferon-α monotherapy, and showed a higher response rate, progression-free survival (PFS), and a trend toward improved OS favoring the combination therapy, making this combination an acceptable first-line treatment for metastatic RCC (other first-line treatment options include the use of VEGF receptor TKIs such as sunitinib and sorafenib or the use of the newer mammalian target of rapamycin [mTOR] inhibitor temsorilimus).43,46,49,91,92 The use of interferon in the adjuvant setting in patients with advanced, but resectable, RCC has shown no advantage over observation alone.48
Melanoma
Early empiric trials treating metastatic melanoma with leukocyte interferon α were disappointing, possibly because of the low doses and the short duration of treatment. Phase I/II clinical trials with recombinant interferon α-2a and interferon α-2b permitted escalation of dose and longer durations of therapy and achieved response rates of 5% to 29% with a median response rate of 19%.50,51,52,53,54,55,56,57,58,59 The Eastern Cooperative Oncology Group Trial EST 1684 was a pivotal trial that established the use of adjuvant interferon α-2b in high-risk patients with deep primary (T4) or locally advanced (N1) melanoma.60 Interferon was the first agent to demonstrate a statistically significant improvement in disease-free survival (DFS) as well as OS in the adjuvant setting. Although the addition of interferon to chemotherapeutic agents such as dacarbazine in metastatic melanoma has yielded increased response rates, no statistically significant improvement in DFS or OS was seen.61,62,63,64 The lack of significant outcome benefit combined with increased toxicity when interferon is used with chemotherapy has prevented its widespread use.
Other Tumors
The use of α interferon in Kaposi sarcoma has yielded response rates of up to 40%, although responses take months to reach maximal effect. When used as monotherapy, very high doses were required to achieve an effect. The combination of interferon with antiretrovirals was investigated because of their synergistic suppression of HIV-1 replication in vitro. Zidovudine in combination with interferon is active in Kaposi sarcoma, with increases in response and toxicity with increasing doses.65,66,67
In an effort to reduce the risk of recurrence, intravesical therapy with various cytotoxic and immunomodulatory drugs after transurethral resection of superficial bladder cancers has been extensively studied. The BCG therapy is widely used in the treatment for superficial bladder cancer; its activity theorized to include the production of interferons.68 The use of interferon has proved to be more active than mitoxantrone but not as effective as mitomycin, as demonstrated in randomized studies.68,69 Interim analysis of a phase II study of BCG with interferon has shown the efficacy and safety of the combination therapy.70
INTERLEUKINS
Like interferons, the interleukins are lymphokines—proteins secreted by leukocytes that affect the growth and the function of other leukocytes. Recombinant interleukin 2 (IL-2) has been the most extensively studied in randomized clinical trials and was approved in 1992 by the U.S. Food and Drug Administration (FDA) based on studies in metastatic renal cell cancer patients.
IL-2 possesses several biologic activities, including augmentation of cytolytic T-cell activity and induction of secretion of other lymphokines, including interferon α and TNF as well as growth factors for B cells and natural killer (NK) cells. In addition, IL-2 induces the proliferation and activation of certain cytolytic effector cells such as NK cells, cytotoxic T lymphocytes, and, in particular, lymphokine-activated killer (LAK) cells. The precursor of LAK cells, found in the peripheral blood, are phenotypically non-B, non-T lymphocytes. Following incubation with IL-2, these precursor cells develop the capacity to lyse tumor cells. These LAK cells represent a subpopulation of null cells and are phenotypically and functionally distinct from NK cells and cytolytic T lymphocytes.
Renal Cell Carcinoma
The activity of IL-2 in metastatic RCC was first described by Rosenberg et al. in the 1980s.71,72 However, in high doses it displayed toxicity manifested as a capillary leak syndrome similar to that seen in septic shock with significant hypotension, pulmonary edema, weight gain, and oliguria.73,74 Administration thus necessitated admission to an ICU. In an attempt to reduce toxicity, studies were undertaken combining IL-2 with interferon in patients with metastatic RCC. Negrier et al. randomized patients to treatment with intravenous recombinant IL-2, subcutaneous recombinant interferon α-2a, or both. Combination therapy afforded a statistically significantly higher event-free survival and response rate; however, no difference in OS was noted among the three regimens. As expected, combination therapy also resulted in increased toxicity.75
However, in a randomized phase III trial by the Cytokine Working Group, a more intensive bolus infusion of IL-2 was compared with subcutaneous IL-2 in combination with interferon α-2a, and high-dose therapy resulted in a higher response rate of 23.2% versus 9.9%. A statistically significant improvement in OS was found in patients with unresected primary tumor with liver or bone metastases.76 The increased response rates of high-dose IL-2 compared with low-dose IL-2 or subcutaneous interferon were also confirmed by National Cancer Institute Surgery Branch investigators, although no survival advantage was noted, and the results attributed to a cohort of patients with better prognostic factors.77 On the basis of in vitro studies suggesting a synergy between interferon α-2a and fluorouracil,78 subcutaneous IL-2 combined with interferon a-2a and fluorouracil did demonstrate a survival advantage over interferon with vinblastine and established the safety of combination therapy.79 In the arena of cytokine therapy for RCC, high-dose IL-2 remains an efficacious option albeit at the cost of increased toxicity. Currently, VEGF receptor TKIs such as sunitinib and sorafenib, and mTOR inhibitors have become the preferred first-line treatment options.
Melanoma
The activity of IL-2 in the treatment for melanoma has been evident since the early studies by Rosenberg et al. as described in the preceding text in which objective response rates of 33% were noted. The potential synergy between interferon and IL-2 was investigated in melanoma as in RCC. In a randomized phase III trial, high-dose IL-2 was administered alone or with interferon a-2a in patients with advanced melanoma with equivalent response rates, median durations of response, and median survival as well as toxicity.80 The question of whether
combining chemotherapy with immunotherapy would result in improved response rates in melanoma has been studied in two randomized trials. The addition of IL-2 (either subcutaneously or at high doses intravenously) to interferon and dacarbazine and cisplatin-based combination chemotherapy did not afford any advantage to chemotherapy alone in patients with metastatic melanoma, resulting only in increased toxicity.81,82
combining chemotherapy with immunotherapy would result in improved response rates in melanoma has been studied in two randomized trials. The addition of IL-2 (either subcutaneously or at high doses intravenously) to interferon and dacarbazine and cisplatin-based combination chemotherapy did not afford any advantage to chemotherapy alone in patients with metastatic melanoma, resulting only in increased toxicity.81,82
TUMOR NECROSIS FACTORS
TNF was so named after its administration to mice with sarcomas resulted in hemorrhagic necrosis of the tumor. It was first derived from the sera of mice primed with BCG and then challenged with endotoxin. Two subtypes of TNF exist: TNF-α, which is produced by monocytes, and TNF-β (also called lymphotoxin), which is produced by stimulated T lymphocytes. Both TNF-α and -β have been cloned and sequenced and are available in recombinant forms. They display a wide array of both metabolic and biologic activities.
Phase I trials have demonstrated toxicity profiles similar to other cytokines/lymphokines with the most common side effects being fever, fatigue, malaise, and hypotension.82,83 Headaches were commonly seen. The maximum tolerated dose with intravenous administration was <350 µg/m2/day and 522 µg per m2 intratumorally, with the dose-limiting toxicities being constitutional symptoms and hypotension.84,85 These phase I trials demonstrated responses in various malignancies including colorectal carcinoma, breast carcinoma, renal carcinoma, and melanoma. However, these responses were disappointing in comparison to the activity of TNF in murine models, which has been attributed to limitation of systemic administration because of hypotension.86
Although its toxicities limited systemic administration, the observations that TNF-α causes hemorrhagic necrosis when given intratumorally, its synergism with interferon, as well as enhancement of its activity by hyperthermia and alkylating agents, led to its use in isolated limb perfusion, a method of local therapy for advanced sarcoma and melanoma. ORRs of 80% to 100% were noted with DFS and OS rates of approximately 70% at 12 months in initial studies.87,88,89 Similar response rates were obtained in patients with extensive regional Kaposi sarcoma.90 On June 2008, the FDA did send an alert to all health care professionals about an increased risk of malignancy (mainly lymphomas and leukemia) and opportunistic infection associated with TNF inhibitor use. Currently, TNF inhibitors are rarely used for any malignancy in the United States.
MONOCLONAL ANTIBODIES
In 1975, Kohler and Milstein described a new technique of producing mAbs.9 In simplistic terms, they took B lymphocytes from mice immunized with sheep RBCs and fused them in vivo with an immortal nonsecretory murine myeloma cell line. Surviving clones, which produced antisheep RBC antibody, could then be grown either in vitro or in the peritoneal cavity of mice. This new hybridoma technique thereby permitted production of milligram quantities of specific and entirely homogeneous mAbs and helped open up new avenues for use of antibodies in cancer diagnosis and therapy. The development of the use of mAbs in cancer therapy has evolved immensely since the initial work of Kohler and Milstein. Several different antibody complexes have been formulated, including chimeric human-murine antibodies comprised of human constant regions and murine variable regions, humanized antibodies with murine complementarity determining region sequences incorporated into human immunoglobulin G (IgG) molecules, and human antibodies from human hybridomas. Transgenic mice expressing human immunoglobulin genes have also been developed.93 The mAbs currently approved by the FDA and their clinical and therapeutic applications will be discussed in detail in the subsequent text.
Anti-CD20 Monocloncal Antibodies: Rituximab and Ofatumumab
The chemical engineering of CD20 mAbs has revolutionized the management of lymphomas and leukemias over the last two decades. Their mechanism of action include complement-dependent cytotoxicity, programmed cell death, and fludarabine plus cyclophosphamide (FC): fludarabine, cyclophosphamide, and rituximab (FCR)-dependent interactions, with passive immunization being a potential fourth mechanism.94
Rituximab
Rituximab, a chimeric mAb directed against the B cell determinant CD20, was the first FDA-approved mAb. Comprised of human IgG2 and k constant regions with murine variable regions, the antibody destroys CD20+ cells through complement-mediated lysis, antibody-dependent cell-mediated cytotoxicity, inhibition of cell proliferation as well as direct apoptosis. In a phase I dose-escalation trial, Maloney et al. demonstrated excellent patient tolerability at doses up to 500 mg per m2 in patients with relapsed low-grade B-cell lymphoma. Infusion-related symptoms such as fever, rigors, and hypotension were correlated with tumor burden, and 2-week post-therapy tumor biopsies demonstrated the mAb to be still bound to CD20 antigen sites.95
Non-Hodgkin’s Lymphoma
In a multicenter, phase II study by Maloney et al., patients with relapsed or refractory low-grade lymphomas were treated with 375 mg per m2 weekly doses of single-agent rituximab for 4 weeks. A response rate of 46% was noted with median time to progression of 10.2 months in those patients who responded. Infusional side effects were mild and observed mostly with the first infusion.96
Given the promising results in low-grade lymphoma patients with single-agent rituximab, the mAb was subsequently tested in patients with more aggressive histologies. An overall ORR of 31% was observed in patients with relapsed or refractory intermediate- or high-grade lymphomas with median time to progression nearing 9 months.97 The chemotherapeutic standard of care for the treatment for non-Hodgkin’s lymphoma (NHL) had been cyclophosphamide, doxorubicin, vincristine, and
prednisone (CHOP). The addition of rituximab with CHOP (R-CHOP) was administered for the first time as de novo therapy to 38 patients with low-grade lymphomas. The ORR was 100%, with 87% achieving a CR. The median time to progression was 82.3 months.98 In previously untreated patients with aggressive NHL, R-CHOP resulted in an ORR of 94% with CRs in 61% of patients. Median time to progression was not reached after a median observation time of 26 months.99
prednisone (CHOP). The addition of rituximab with CHOP (R-CHOP) was administered for the first time as de novo therapy to 38 patients with low-grade lymphomas. The ORR was 100%, with 87% achieving a CR. The median time to progression was 82.3 months.98 In previously untreated patients with aggressive NHL, R-CHOP resulted in an ORR of 94% with CRs in 61% of patients. Median time to progression was not reached after a median observation time of 26 months.99
The promising results of these phase II studies led to comparison of R-CHOP versus traditional CHOP in randomized, phase III studies. The German Low-Grade Lymphoma Group randomized patients with advanced-stage follicular lymphoma (FL) to R-CHOP or CHOP alone for six to eight cycles. The addition of rituximab to CHOP reduced the relative risk for treatment failure by 60% with a higher ORR and prolonged durations of remission, both statistically significant. OS was also statistically significantly improved. In the first 3 years after therapy, 6 deaths were noted in the R-CHOP group, whereas 17 deaths occurred in the patients who received CHOP alone.100 Long-term results from a randomized, phase III study involving elderly patients with diffuse large B-cell lymphoma demonstrated a statistically significant advantage in OS, as well as disease-free survival in favor of the group receiving R-CHOP versus CHOP alone.101
Chronic Lymphocytic Leukemia
Several groups evaluated rituximab in combination with chemotherapy agents active against chronic lymphocytic leukemia (CLL). The Cancer and Leukemia Group B treated 104 treatment naive patients with fludarabine with or without rituximab. The results showed that the combination arm had a higher ORR of 90%, compared with 77% for the fludarabine-only arm. The CR rate was 47% in the combination arm and 28% in the fludarabine-only arm.102,103,110
The group from MD Anderson designed a regimen of FCR (fludarabine 25 mg per m2, cyclophosphamide 250 mg per m2 daily for 3 days, and rituximab 375 mg per m2 on Day 1 of cycle 1 and 500 mg per m2 on day 1 of cycles 2 to 6). FCR was given to 177 patients with relapsed or refractory CLL.102 Therapy with FCR yielded an OR rate of 73% and a CR in 25% of patients, of whom 32% also had a complete molecular response. The German CLL Group compared FCR and FC in a large phase III randomized trial (CLL8). Eight hundred seventeen treatment naive patients with CLL were randomized 1:1 to FCR or FC alone. FCR induced a higher OR (95% vs. 88%) and more CRs (52% vs. 27%; P < .0001) than FC, as well as an improved PFS of 52 months versus 33 months for the FC group (P < .001) and improved OS compared with those in the FC arm. At 38 months, patients in the FCR arm had an OS of 84% versus 79% (P = .01) in the FC arm. FCR is currently considered to be the standard of care for front-line management of advanced CLL by the German CLL Study Group.104
Other Malignancies
Thomas and colleagues reported their experience in patients with de novo Burkitt lymphoma and acute lymphoblastic leukemia treated with the combination of hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone alternating with methotrexate and cytarabine) and rituximab. The results favored the addition of rituximab with the historical controls.105,106
Ofatumumab
Ofatumumab is a humanized anti-CD20 mAb that was approved by the FDA in October 2009 for treatment for CLL. The clinical efficacy and safety of single-agent ofatumumab has been demonstrated in two phase I-II trials of relapsed/refractory CLL (some patients had progression after getting fludarabine and alemtuzumab) and FL, and phase III trials are ongoing. Combination chemotherapy of ofatumumab 500 mg or 1,000 mg with fludarabine and cyclophosphamide was investigated in previously untreated patients with CLL in an international randomized phase II trial. This regimen showed high activity in untreated CLL patients with CR of 32% for those who received 500 mg of ofatumumab compared with 50% for those who received 1,000 mg; the ORR was 77% and 73%, respectively. No grade 3 to 4 infusion-related reactions were reported.107,108,109,110
Iodine 131I Tositumomab and Yttrium 90Y Ibritumomab Tiuxetan
The next mAbs to be introduced to the market were iodine 131 (131I) tositumomab and yttrium 90 (90Y) ibritumomab tiuxetan (IDEC-Y2B8), which offered novel cancer therapy in the form of radioimmunotherapy. Radioimmunotherapy utilizes an mAb with the intent of targeting radiation to malignant tissue while sparing normal cells. 131I tositumomab is a radiolabeled immunoglobulin IgG-2a murine mAb directed against the CD20 antigen. 131I was initially chosen as the radio conjugate secondary to several of its properties. Its β emission allows radiation to be delivered to malignant cells with the target as well as adjacent cells, which, although not expressing the antigen, may nonetheless be part of the malignant clone. 131I also produces γ emissions allowing total-body γ counts to be obtained, a process necessary for dosimetry.111 Vose et al. enrolled 47 patients with relapsed or refractory low-grade, or transformed low-grade NHL onto a phase II study evaluating response rate and dosimetry of 131I tositumomab. On day zero, study participants received 450 mg unlabeled tositumomab with 35 mg of 5 microcuries (mCi) 131I tositumomab. The purpose of the administration of the unlabeled mAb was to saturate the antigen sink thought to exist in the peripheral blood, bone marrow, and spleen on Days 0 to 7, daily whole-body γ counts were obtained. The therapeutic dose was administered 7 to 14 days after the dosimetric dose such that 75 cGy of radiation was delivered to the patient. A 57% response rate with a CR rate of 32% and a median duration of response of 9.9 months was found; a significant result considering that the median number of prior chemotherapeutic regimens was four and 87% of patients had at least two high-risk factors as outlined in the International Prognostic Index.112 The most common toxicity was hematologic, although fatigue, nausea, and fever were the predominant nonhematologic toxicities. The dosing and treatment procedures were validated in this study by centers with experience in the calculations and were corroborated.113
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