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Cancer Therapy Vol 6, page 181 Cancer Therapy Vol 6, 181-186, 2008 Chemoimmunotherapy for canine lymphoma: tumor vaccines and monoclonal antibodies Review Article Steven E. Crow VCA Sacramento Veterinary Referral Center and VCA Highlands Animal Hospital, CA, USA __________________________________________________________________________________ *Correspondence: Steven E. Crow, DVM. VCA Sacramento Veterinary Referral Center, 9801 Old Winery Place, Sacramento, CA 95827, USA; Tel: (916) 362-3111 VCA Highlands Animal Hospital, Cancer Treatment Center, 3451 Elkhorn Blvd, North Highlands, CA 95660, USA; Tel: (916) 332- 2845; e-mail: firstname.lastname@example.org Key words: Chemoimmunotherapy, canine lymphoma tumor vaccines, canine lymphoma tumor vaccines, Canine Abbreviations: complete response, (CR); monoclonal antibodies, (MAb); non-Hodgkin's lymphoma, (NHL); overall response rate, (ORR); radioimmunoconjugates, (RICs); radioimmunotherapy, (RIT) Received: 10 March 2008; electronically published: June 2008 Presented in the Theilen Tribute Symposium at UC Davis 31 st May- 1st June 2008. Summary Despite numerous clinical trials with drugs that reliably induce remission, cure for most cases of canine lymphoma has continued to elude veterinary oncologists over the last 40 years. Results of various chemotherapy protocols are remarkably similar, and no breakthrough drugs have been discovered. Although trials employing biological response modifiers have been few in number and small in size, results of those studies are reason for optimism. Favorable outcomes with tumor vaccines in canine lymphoma and monoclonal antibodies in human non-Hodgkin lymphoma support the need for additional studies of immunotherapeutic interventions in this common and devastating disease. I. Introduction II. Review of results Lymphoma is the most common neoplasm of the A. Canine canine hemolymphatic system. It represents approximately In the early 1970s, Benjamini and others 4.5% of all canine neoplasms and 15% of all malignant demonstrated significant delay in recurrence and neoplasms. Canine lymphoma (CL) is usually rapidly progression of tumors in laboratory mice treated with fatal, resulting in death within one to three months of surgery and chemically-modified tumor cell vaccine diagnosis (Squire et al, 1973). Temporary remission of compared to mice treated with surgical excision only clinical signs without treatment is rare. Most CL cases are (Thompson et al, 1972; Benjamini, Scibienski 1974; high or intermediate histologic grade; less aggressive, low- Benjamini et al, 1976). Subsequently, Theilen and Worley grade lymphoma represents less than 5% of all CL cases conducted a preliminary clinical investigation in which 20 reported (Squire et al, 1973; Schwartz 1988; Rosenberg dogs given a similar vaccine had markedly improved mean 1991; Teske et al, 1994). Treatment of CL has been a topic survival times (341 days) versus 47 dogs treated with of great interest for veterinary oncologists for almost 40 chemotherapy only (138 days) (Theilen et al, 1977). years. The principal mode of medical management has From 1974 through 1977, our research team, led by been chemotherapy (Rosenthal 1990; Jeglum and Dr. Gordon Theilen, completed two prospective, Steplewski, 1996) but various attempts at immunotherapy randomized clinical trials (Crow et al, 1977, Weller et al, (biological response modification) have produced results 1980) in which we compared dogs treated for multicentric that rival or surpass outcomes with drugs alone (Table 1) lymphoma with combination chemotherapy, followed by (Crow et al, 1977, 1996; Theilen et al, 1977; Weller et al, injections of placebo or autogenous tumor vaccine. In the 1980; Jeglum et al, 1986, 1988; Jeglum and Steplewski, first study, dogs with lymphoma had a single lymph node 1996). excised prior to receiving a nine-week combination chemotherapy protocol. Dogs that achieved and 181 Crow: Chemoimmunotherapy for canine lymphoma: tumor vaccines and monoclonal antibodies maintained complete remission throughout induction were et al, 1972; Prager and Baechtel, 1973; Benjamini and then injected intramuscularly with either tumor vaccine, Scibienski, 1974; Witney et al, 1974; Benjamini et al, consisting of acetoacetylated tumor cell wall proteins 1976; Rosenthal and MacEwen, 1990). Dogs receiving suspended in complete Freund's complete adjuvant vaccine achieved median first remission and overall (Figure 1), or placebo. Individual vaccine was produced survival times of 132 and 336 days, respectively, for each test dog from its own lymphoma cells. Tumor cell compared to 91 and 196 for dogs receiving placebo membrane protein alterations and immunoadjuvant were injections (Figures 2, 3) (Crow et al, 1977). Weller and designed to abrogate blocking antibody formation and to colleagues later reported similar results in 32 dogs treated induce cell-mediated immunity (Harris and Copeland, with chemotherapy and various components of the vaccine 1964; Eilber and Morton, 1970; Smith and Adler, 1970; (median first remission = 136 days; median survival = 334 Sjogren et al, 1971; Currie and Basham, 1972; Thompson days) (Weller et al, 1980). Table 1. Comparison of chemotherapy only to chemoimmunotherapy protocols for treatment of intermediate and high grade canine lymphoma. Reference/Study Chemotherapy only Chemoimmunotherapy Median survival (days) Median survival (days) Theilen et al, 1977 138 (n=47) 341(n=20) Crow et al, 1977 196 (n=9) 336 (n=12) Weller et al, 1980 NR 334 (n=32) Jeglum et al, 1988 180 (n=30) 305 (n=56) Jeglum, Steplewski 1996 NR 410 (n=215) Crow et al, 1996 NR 301 (n=85) NR = not reported; historical control used for comparison. Using intralymphatic autochthonous tumor cell vaccine after remission induction with combination chemotherapy, Jeglum achieved a median survival time of 305 days in 56 dogs with lymphoma, compared to 180 days in a control group (n=30) that received only eight weeks of chemotherapy (Jeglum et al, 1988). In the mid-1980s, using the novel hybridoma technology of Kohler and Milstein (Figure 4), several investigators set out to produce monoclonal antibodies (MAb) that could be used for the detection, classification, and treatment of canine lymphoma. In contrast to the nonspecific nature of most chemotherapy, MAb bind with high specificity to cell-surface antigens, resulting in targeted killing of malignant cells, relative sparing of normal tissues, and low toxicity. Using an established canine lymphoma cell line, Jeglum and collaborators at the Wistar Institute produced a panel of murine monoclonal antibodies. They identified a specific monoclonal antibody (CL/MAb 231) that selectively bound to formalin-fixed, paraffin-embedded tumor tissue from 75% of dogs with lymphoma. In addition, this antibody demonstrated cytotoxicity against lymphoma cells in vitro and in vivo (Steplewski et al, 1987; Rosales et al, 1988; Jeglum and Steplewski al 1996). After a Phase I trial demonstrated no significant toxicity, a clinical trial of 215 previously untreated dogs with lymphoma was conducted. An immunoperoxidase assay for CL/MAb 231 binding was performed retrospectively on biopsy specimens from 129 of the dogs in that trial. Complete remission induction rate was 80.5%. Overall median survival was 410 days. Median survival times for non-responders (n=41) and dogs achieving remission and Figure 1. Schematic representation of method used to produce subsequently treated with CL/MAb 231 (n=174) were 113 autogenous canine lymphoma vaccine. Reproduced from Crow et al, 1977 with kind permission from Cancer. days and 493 days, respectively (Jeglum and Steplewski, 1996). 182 Cancer Therapy Vol 6, page 183 Figure 2. First remission duration for dogs receiving chemotherapy and placebo compared to dogs treated with chemotherapy and autogenous tumor vaccine. Reproduced from Crow et al, 1977 with kind permission from Cancer. Figure 3. Survival duration for dogs receiving chemotherapy and placebo compared to dogs treated with chemotherapy and autogenous tumor vaccine. Reproduced from Crow et al, 1977 with kind permission from Cancer. A prospective multi-institutional study was binding were provided for only 25 cases: 20 were strongly conducted to evaluate the effectiveness of CL/MAb 231 positive, 3 were weakly positive, and 2 were negative. with alternative chemotherapy protocols (Crow et al, Because of the small number of non-binders, statistical 1996). Between June 1992 and January 1994, dogs with analysis was not done. Interestingly, one of the non- lymphoma were randomized to receive combination binders was the longest survivor. chemotherapy or single-agent doxorubicin, followed by immunotherapy (CL/MAb 231). Tissue was submitted for B. Human immunoperoxidase binding assay on 65 of the 87 dogs Therapeutic options for human beings with NHL admitted to the trial. Dogs in the doxorubicin only group have improved over the past 20 years, but almost all achieved complete remission much less often than the patients with low-grade lymphoma and approximately combination chemotherapy dogs, but if remission was 50% of patients with high-grade lymphoma eventually die accomplished, remission and survival durations were not of their disease, regardless of the regimen used. Thus, significantly different. Overall median survival was 301 there is a continuing need for novel therapeutic options. days (range = 8 -1022 days); median survival times for the Two such strategies are unconjugated MAb and MAb doxorubicin and combination chemotherapy groups were conjugated to radionuclides, i.e., targeted 259 (range = 1 - 630 days) and 335 days (range = 8 - radioimmunotherapy (RIT). 1022), respectively. Written reports for immunoperoxidase 183 Crow: Chemoimmunotherapy for canine lymphoma: tumor vaccines and monoclonal antibodies Figure 4. Schematic representation of hybridoma production. In 1997, rituximab (Rituxan, Genentech Inc, South relapsed, low-grade B-cell NHL. It is comprised of the San Francisco, California, USA, and Biogen Idec Inc, murine IgG1 anti-CD20 antibody ibritumomab covalently Cambridge, Massachusetts, USA) became the first MAb linked to the beta-emitter yttrium-90 (90Y) by a chelator, approved by the US Food and Drug Administration for use tiuxetan. Tositumomab is a murine IgG2a lambda in the treatment of cancer, specifically B-cell non- monoclonal antibody covalently linked to iodine-131 (131I). Hodgkin's lymphoma. Rituximab has become a staple in Both agents have demonstrated high anti-tumor activity in the management of B-cell non-Hodgkin's lymphoma, but it patients who are refractory to rituximab (Juweid, 2002; has limited activity as a single agent, with responses in Forero and Lobuglio 2003; Horning, 2003; Marcus, 2005; about half of recurrent follicular and low-grade lymphoma Witzig, 2006). Mechanisms of action appear to include patients (Juweid, 2002; Forero and Lobuglio, 2003; apoptosis, complement-dependent cytotoxicity, and Horning, 2003; Marcus, 2005; Witzig, 2006). In hopes of antibody-dependent cellular cytotoxicity. In addition, the using rituximab in the treatment of canine lymphoma, attached radionuclide may kill tumor cells as well as Impellizeri et al, evaluated canine B-cell binding and adjacent normal cells from crossfire or “bystander” effect depletion by rituximab using flow cytometry. Despite (Witzig, 2006). immunohistochemistry demonstration of CD20 A prospective trial comparing 90Y-ibritumomab expression, rituximab did not bind or deplete canine B tiuxetan with single-agent rituximab showed an overall cells ex vivo. They concluded that rituximab is unlikely to response rate (ORR) of 80% (34% complete response be effective in the treatment of canine lymphoma [CR]) for 90Y-ibritumomab tiuxetan compared with an (Impellizeri et al, 2006). ORR of 56% (20% CR) for rituximab (P = .002) (Marcus, RIT is a particularly attractive approach for B-cell 2005). Of patients achieving a CR, 32% were still in lymphoma because CD20 affords an outstanding target remission at 3 to 4 years of follow-up. Similar efficacy and lymphoma cells are inherently radiosensitive. Both (83% ORR, 43% CR) has been reported with 90Y- efficacy and safety of RIT have been established in the ibritumomab tiuxetan in patients with relapsed or treatment of relapsed or refractory indolent non-Hodgkin's refractory low-grade NHL with mild thrombocytopenia lymphoma (NHL) (Juweid, 2002; Forero and Lobuglio and in patients with rituximab-refractory NHL (Marcus, 2003; Horning 2003; Marcus, 2005; Witzig, 2006). The 2005). RIT is very well tolerated and is delivered on an two most commonly used MAb radioimmunoconjugates outpatient basis over 1 week. The only significant toxicity (RICs), ibritumomab tiuxetan (Zevalin, Biogen Idec Inc, is reversible myelosuppression (Marcus, 2005, Witzig, San Diego, California, USA, and Schering AG, Berlin, 2006). Germany) and tositumomab (Bexxar, GlaxoSmithKline, Other RICs are being investigated for the treatment Brentford, Middlesex, United Kingdom) target the CD20 of NHL, as are several immunotoxins. The role of RIT in antigen on B-cells. The former was the first first-line therapy of indolent NHL and in diffuse large B- radioimmunotherapy agent to be approved by the US Food cell lymphoma is still to be determined (Juweid, 2002; and Drug Administration for the treatment of patients with Forero and Lobuglio, 2003; Horning, 2003; Witzig, 2006). 184 Cancer Therapy Vol 6, page 185 II. Discussion Brooks MB, Matus RE, Leifer CE, Patnaik AK. (1987) Use of splenectomy in the management of lymphoma in dogs: 16 Many studies of combination chemotherapy cases (1975-1985). J Am Vet Med Assoc 191:1008-1010. protocols for canine lymphoma have been reported in the Carter RF, Harris CK, Withrow SJ, Valli VE, Susaneck SJ last four decades (Brick et al, 1968; Madewell, 1972; (1987) Chemotherapy of canine lymphoma with MacEwen et al, 1981; Cotter, 1983; Brooks et al, 1987; histopathological correlation: doxorubicin alone compared to Carter et al, 1987; Cotter and Goldstein, 1987; MacEwen COP as first treatment regimen. J Am Anim Hosp Assoc 23, et al, 1987; Rosales et al, 1988; Postorino et al, 1989; 587-596. Rogers, 1989; Greenlee et al, 1990; Rosenthal, 1990; Cotter SM (1983) Treatment of lymphoma and leukemia with Rosenthal and MacEwen, 1990; Klein, 1991; Ogilvie et al, cyclophosphamide, vincristine, and prednisone: I. treatment 1991; Price et al, 1991; Stone et al, 1991; Hahn et al, of dogs. J Am Anim Hosp Assoc 19, 159-165. Cotter SM, Goldstein MA (1987) Comparison of two protocols 1992; MacEwen et al, 1992; Novotney et al, 1992; Keller for maintenance of remission of dogs with lymphoma. J Am et al, 1993; Vail, 1993; Dobson and Gorman, 1994; Anim Hosp Assoc 23, 495-99. Matherne et al, 1994; Moore et al, 1994; Ruslander et al, Crow SE, Rogers KS, Barton CL, Knapp DM, Morrison WE, 1994), but little progress has been made in the overall Susaneck SJ, Jeglum KA, Raskin RE, Fox LM (1996) survival of dogs with this common malignancy. Novel Veterinary Cancer Society Collaborative Clinical Trial-CL- approaches, including whole body hyperthermia, half- MAb231. Unpublished data. body radiation therapy (Laing et al, 1989), continuous low Crow SE, Theilen GH, Benjamini E, Torten M, Henness AM, dose chemotherapy (Rosenthal, 1990; Ogilvie et al, 1991), Buhles WC (1977) Chemoimmunotherapy for canine lymphosarcoma. Cancer 40, 2102-2108. bone marrow transplantation (Rosenthal, 1990) and Currie, GA, Basham C (1972) Serum-mediated inhibition of the nutritional intervention (Williams, 1988) have been immunological reaction of the patient to his own tumor-a attempted, but case accessions have been quite small in possible role for circulating antigen. Br J Cancer 26, 427- most trials. 430. In retrospect, it is disappointing that evaluation of Dobson JM, Gorman NT (1994) Canine multicentric lymphoma CL/MAb 231 by independent investigators was not 2: Comparison of response to two chemotherapeutic completed prior to its commercial release. Questions of protocols. J Small Anim Pract 35, 9-15. binding sensitivity and specificity as well as retention of Eilber FR, Morton DL (1970) Impaired immunological reactivity efficacy with continued passage remained unanswered and recurrence following cancer surgery. Cancer 25, 362- 367. when production was discontinued, presumably for Forero A, Lobuglio AF (2003) History of antibody therapy for financial considerations. non-Hodgkin's lymphoma. Semin Oncol 30, 1-5. Anecdotally, during the last 34 years I have Greenlee PG, Filippa DA, Quimby FW, Patnaik AK, Calvano personally treated more than 1900 dogs with intermediate SE, Matus RE, Kimmel M, Hurvitz AI, Lieberman PH or high grade multicentric lymphoma (stages III-V) using (1990) Lymphoma in dogs. A morphologic, immunologic, various combination chemotherapy protocols. Only 18 and clinical study. Cancer 66, 480-490. dogs have been “cured”, i.e., survived longer than three Hahn KA, Richardson RC, Teclaw RF, Cline JM, Carlton WW, years and died free of any signs of lymphoma. All but two DeNicola DB, Bonney PL. (1992) Is maintenance of those dogs never relapsed after the initial induction chemotherapy appropriate for the management of canine malignant lymphoma? J Vet Intern Med 6, 3-10. chemotherapy. Interestingly, seven of the 18 dogs were Harris J, Copeland D (1964) Impaired immunoresponsiveness in treated with CL/MAb 231 and five dogs received either tumor patients. Ann NY Acad Sci 120, 56-75. Freund's complete adjuvant or autogenous tumor vaccine Horning SJ (2003) Future directions in radioimmunotherapy for injections. B-cell lymphoma. Semin Oncol 30, 29-34. Unfortunately, the search for magic potions (drugs) Impellizeri JA, Howell K, McKeever KP, Crow SE (2006) The has been surprisingly unfruitful over the last three decades. role of rituximab in the treatment of canine lymphoma: an ex The documented success of therapeutic monoclonal vivo evaluation. Vet J 171, 556-8. antibodies for human non-Hodgkin’s lymphoma, clearly Jeglum KA, Steplewski Z (1996). Chemoimmunotherapy of highlights the opportunity that was missed by veterinary canine lymphoma with adjuvant canine monoclonal antibody 231. Vet Clin N Amer Sm Anim Pract 26, 73-85. oncologists. 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