Chemoimmunotherapy for canine lymphoma tumor vaccines and

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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: steve.crow@vcamail.com
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


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              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).


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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


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              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).


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                                              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. It is my hope that the new generation of
                                                                      Jeglum KA, Young KM, Barnsley K, Whereat A (1988)
veterinary oncologists will look again at immune targeting                Chemotherapy versus chemotherapy with intralymphatic
and immunomodulation as possible paths toward cure of                     tumor cell vaccine in canine lymphoma. Cancer 61, 2042-
this devastating cancer.                                                  2050.
                                                                      Jeglum KA, Young KM, Bransley K, Whereat A, McGrath D,
                                                                          Hutson C (1986) Intralymphatic autochthonous tumor cell
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                                                                                                Steven E. Crow
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