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) 3322845; 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.

II. Review of results

A. Canine

I. Introduction
Lymphoma is the most common neoplasm of the
canine hemolymphatic system. It represents approximately
4.5% of all canine neoplasms and 15% of all malignant
neoplasms. Canine lymphoma (CL) is usually rapidly
fatal, resulting in death within one to three months of
diagnosis (Squire et al, 1973). Temporary remission of
clinical signs without treatment is rare. Most CL cases are
high or intermediate histologic grade; less aggressive, lowgrade lymphoma represents less than 5% of all CL cases
reported (Squire et al, 1973; Schwartz 1988; Rosenberg
1991; Teske et al, 1994). Treatment of CL has been a topic
of great interest for veterinary oncologists for almost 40
years. The principal mode of medical management has
been chemotherapy (Rosenthal 1990; Jeglum and
Steplewski, 1996) but various attempts at immunotherapy
(biological response modification) have produced results
that rival or surpass outcomes with drugs alone (Table 1)
(Crow et al, 1977, 1996; Theilen et al, 1977; Weller et al,
1980; Jeglum et al, 1986, 1988; Jeglum and Steplewski,
1996).

In the early 1970s, Benjamini and others

demonstrated significant delay in recurrence and
progression of tumors in laboratory mice treated with
surgery and chemically-modified tumor cell vaccine
compared to mice treated with surgical excision only
(Thompson et al, 1972; Benjamini, Scibienski 1974;
Benjamini et al, 1976). Subsequently, Theilen and Worley
conducted a preliminary clinical investigation in which 20
dogs given a similar vaccine had markedly improved mean
survival times (341 days) versus 47 dogs treated with
chemotherapy only (138 days) (Theilen et al, 1977).
From 1974 through 1977, our research team, led by
Dr. Gordon Theilen, completed two prospective,
randomized clinical trials (Crow et al, 1977, Weller et al,
1980) in which we compared dogs treated for multicentric
lymphoma with combination chemotherapy, followed by
injections of placebo or autogenous tumor vaccine. In the
first study, dogs with lymphoma had a single lymph node
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
then injected intramuscularly with either tumor vaccine,
consisting of acetoacetylated tumor cell wall proteins
suspended in complete Freund's complete adjuvant
(Figure 1), or placebo. Individual vaccine was produced
for each test dog from its own lymphoma cells. Tumor cell
membrane protein alterations and immunoadjuvant were
designed to abrogate blocking antibody formation and to
induce cell-mediated immunity (Harris and Copeland,
1964; Eilber and Morton, 1970; Smith and Adler, 1970;
Sjogren et al, 1971; Currie and Basham, 1972; Thompson

et al, 1972; Prager and Baechtel, 1973; Benjamini and

Scibienski, 1974; Witney et al, 1974; Benjamini et al,
1976; Rosenthal and MacEwen, 1990). Dogs receiving
vaccine achieved median first remission and overall
survival times of 132 and 336 days, respectively,
compared to 91 and 196 for dogs receiving placebo
injections (Figures 2, 3) (Crow et al, 1977). Weller and
colleagues later reported similar results in 32 dogs treated
with chemotherapy and various components of the vaccine
(median first remission = 136 days; median survival = 334
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
Theilen et al, 1977
Crow et al, 1977
Weller et al, 1980
Jeglum et al, 1988
Jeglum, Steplewski 1996
Crow et al, 1996

Chemotherapy only
Median survival (days)
138 (n=47)
196 (n=9)
NR
180 (n=30)
NR
NR

Chemoimmunotherapy
Median survival (days)
341(n=20)
336 (n=12)
334 (n=32)
305 (n=56)
410 (n=215)
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
subsequently treated with CL/MAb 231 (n=174) were 113
days and 493 days, respectively (Jeglum and Steplewski,
1996).

Figure 1. Schematic representation of method used to produce

autogenous canine lymphoma vaccine. Reproduced from Crow et
al, 1977 with kind permission from Cancer.

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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

conducted to evaluate the effectiveness of CL/MAb 231
with alternative chemotherapy protocols (Crow et al,
1996). Between June 1992 and January 1994, dogs with
lymphoma were randomized to receive combination
chemotherapy or single-agent doxorubicin, followed by
immunotherapy (CL/MAb 231). Tissue was submitted for
immunoperoxidase binding assay on 65 of the 87 dogs
admitted to the trial. Dogs in the doxorubicin only group
achieved complete remission much less often than the
combination chemotherapy dogs, but if remission was
accomplished, remission and survival durations were not
significantly different. Overall median survival was 301
days (range = 8 -1022 days); median survival times for the
doxorubicin and combination chemotherapy groups were
259 (range = 1 - 630 days) and 335 days (range = 8 1022), respectively. Written reports for immunoperoxidase

binding were provided for only 25 cases: 20 were strongly

positive, 3 were weakly positive, and 2 were negative.
Because of the small number of non-binders, statistical
analysis was not done. Interestingly, one of the nonbinders was the longest survivor.

B. Human
Therapeutic options for human beings with NHL
have improved over the past 20 years, but almost all
patients with low-grade lymphoma and approximately
50% of patients with high-grade lymphoma eventually die
of their disease, regardless of the regimen used. Thus,
there is a continuing need for novel therapeutic options.
Two such strategies are unconjugated MAb and MAb
conjugated
to
radionuclides,
i.e.,
targeted
radioimmunotherapy (RIT).

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Figure 4. Schematic representation of hybridoma production.

In 1997, rituximab (Rituxan, Genentech Inc, South

San Francisco, California, USA, and Biogen Idec Inc,
Cambridge, Massachusetts, USA) became the first MAb
approved by the US Food and Drug Administration for use
in the treatment of cancer, specifically B-cell nonHodgkin's lymphoma. Rituximab has become a staple in
the management of B-cell non-Hodgkin's lymphoma, but it
has limited activity as a single agent, with responses in
about half of recurrent follicular and low-grade lymphoma
patients (Juweid, 2002; Forero and Lobuglio, 2003;
Horning, 2003; Marcus, 2005; Witzig, 2006). In hopes of
using rituximab in the treatment of canine lymphoma,
Impellizeri et al, evaluated canine B-cell binding and
depletion by rituximab using flow cytometry. Despite
immunohistochemistry
demonstration
of
CD20
expression, rituximab did not bind or deplete canine B
cells ex vivo. They concluded that rituximab is unlikely to
be effective in the treatment of canine lymphoma
(Impellizeri et al, 2006).
RIT is a particularly attractive approach for B-cell
lymphoma because CD20 affords an outstanding target
and lymphoma cells are inherently radiosensitive. Both
efficacy and safety of RIT have been established in the
treatment of relapsed or refractory indolent non-Hodgkin's
lymphoma (NHL) (Juweid, 2002; Forero and Lobuglio
2003; Horning 2003; Marcus, 2005; Witzig, 2006). The
two most commonly used MAb radioimmunoconjugates
(RICs), ibritumomab tiuxetan (Zevalin, Biogen Idec Inc,
San Diego, California, USA, and Schering AG, Berlin,
Germany) and tositumomab (Bexxar, GlaxoSmithKline,
Brentford, Middlesex, United Kingdom) target the CD20
antigen on B-cells. The former was the first
radioimmunotherapy agent to be approved by the US Food
and Drug Administration for the treatment of patients with

relapsed, low-grade B-cell NHL. It is comprised of the

murine IgG1 anti-CD20 antibody ibritumomab covalently
linked to the beta-emitter yttrium-90 (90Y) by a chelator,
tiuxetan. Tositumomab is a murine IgG2a lambda
monoclonal antibody covalently linked to iodine-131 (131I).
Both agents have demonstrated high anti-tumor activity in
patients who are refractory to rituximab (Juweid, 2002;
Forero and Lobuglio 2003; Horning, 2003; Marcus, 2005;
Witzig, 2006). Mechanisms of action appear to include
apoptosis, complement-dependent cytotoxicity, and
antibody-dependent cellular cytotoxicity. In addition, the
attached radionuclide may kill tumor cells as well as
adjacent normal cells from crossfire or bystander effect
(Witzig, 2006).
A prospective trial comparing 90Y-ibritumomab
tiuxetan with single-agent rituximab showed an overall
response rate (ORR) of 80% (34% complete response
[CR]) for 90Y-ibritumomab tiuxetan compared with an
ORR of 56% (20% CR) for rituximab (P = .002) (Marcus,
2005). Of patients achieving a CR, 32% were still in
remission at 3 to 4 years of follow-up. Similar efficacy
(83% ORR, 43% CR) has been reported with 90Yibritumomab tiuxetan in patients with relapsed or
refractory low-grade NHL with mild thrombocytopenia
and in patients with rituximab-refractory NHL (Marcus,
2005). RIT is very well tolerated and is delivered on an
outpatient basis over 1 week. The only significant toxicity
is reversible myelosuppression (Marcus, 2005, Witzig,
2006).
Other RICs are being investigated for the treatment
of NHL, as are several immunotoxins. The role of RIT in
first-line therapy of indolent NHL and in diffuse large Bcell lymphoma is still to be determined (Juweid, 2002;
Forero and Lobuglio, 2003; Horning, 2003; Witzig, 2006).

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Brooks MB, Matus RE, Leifer CE, Patnaik AK. (1987) Use of
splenectomy in the management of lymphoma in dogs: 16
cases (1975-1985). J Am Vet Med Assoc 191:1008-1010.
Carter RF, Harris CK, Withrow SJ, Valli VE, Susaneck SJ
(1987) Chemotherapy of canine lymphoma with
histopathological correlation: doxorubicin alone compared to
COP as first treatment regimen. J Am Anim Hosp Assoc 23,
587-596.
Cotter SM (1983) Treatment of lymphoma and leukemia with
cyclophosphamide, vincristine, and prednisone: I. treatment
of dogs. J Am Anim Hosp Assoc 19, 159-165.
Cotter SM, Goldstein MA (1987) Comparison of two protocols
for maintenance of remission of dogs with lymphoma. J Am
Anim Hosp Assoc 23, 495-99.
Crow SE, Rogers KS, Barton CL, Knapp DM, Morrison WE,
Susaneck SJ, Jeglum KA, Raskin RE, Fox LM (1996)
Veterinary Cancer Society Collaborative Clinical Trial-CLMAb231. Unpublished data.
Crow SE, Theilen GH, Benjamini E, Torten M, Henness AM,
Buhles WC (1977) Chemoimmunotherapy for canine
lymphosarcoma. Cancer 40, 2102-2108.
Currie, GA, Basham C (1972) Serum-mediated inhibition of the
immunological reaction of the patient to his own tumor-a
possible role for circulating antigen. Br J Cancer 26, 427430.
Dobson JM, Gorman NT (1994) Canine multicentric lymphoma
2: Comparison of response to two chemotherapeutic
protocols. J Small Anim Pract 35, 9-15.
Eilber FR, Morton DL (1970) Impaired immunological reactivity
and recurrence following cancer surgery. Cancer 25, 362367.
Forero A, Lobuglio AF (2003) History of antibody therapy for
non-Hodgkin's lymphoma. Semin Oncol 30, 1-5.
Greenlee PG, Filippa DA, Quimby FW, Patnaik AK, Calvano
SE, Matus RE, Kimmel M, Hurvitz AI, Lieberman PH
(1990) Lymphoma in dogs. A morphologic, immunologic,
and clinical study. Cancer 66, 480-490.
Hahn KA, Richardson RC, Teclaw RF, Cline JM, Carlton WW,
DeNicola DB, Bonney PL. (1992) Is maintenance
chemotherapy appropriate for the management of canine
malignant lymphoma? J Vet Intern Med 6, 3-10.
Harris J, Copeland D (1964) Impaired immunoresponsiveness in
tumor patients. Ann NY Acad Sci 120, 56-75.
Horning SJ (2003) Future directions in radioimmunotherapy for
B-cell lymphoma. Semin Oncol 30, 29-34.
Impellizeri JA, Howell K, McKeever KP, Crow SE (2006) The
role of rituximab in the treatment of canine lymphoma: an ex
vivo evaluation. Vet J 171, 556-8.
Jeglum KA, Steplewski Z (1996). Chemoimmunotherapy of
canine lymphoma with adjuvant canine monoclonal antibody
231. Vet Clin N Amer Sm Anim Pract 26, 73-85.
Jeglum KA, Young KM, Barnsley K, Whereat A (1988)
Chemotherapy versus chemotherapy with intralymphatic
tumor cell vaccine in canine lymphoma. Cancer 61, 20422050.
Jeglum KA, Young KM, Bransley K, Whereat A, McGrath D,
Hutson C (1986) Intralymphatic autochthonous tumor cell
vaccine in canine lymphoma. J Bio Resp Mod 5, 168-175.
Juweid ME (2002) Radioimmunotherapy of B-cell nonHodgkin's lymphoma: from clinical trials to clinical practice.
J Nucl Med 43, 1507-29.
Keller ET, MacEwen EG, Rosenthal RC, Helfand SC, Fox LE
(1993) Evaluation of prognostic factors and sequential
combination chemotherapy with doxorubicin for canine
lymphoma. J Vet Intern Med 7, 289-295.
Klein MK (1991) The effect of previous corticosteroid exposure
on response to doxorubicin in canine lymphoma patients. Vet
Can Soc Newsletter 15, 22-23.

II. Discussion
Many studies of combination chemotherapy
protocols for canine lymphoma have been reported in the
last four decades (Brick et al, 1968; Madewell, 1972;
MacEwen et al, 1981; Cotter, 1983; Brooks et al, 1987;
Carter et al, 1987; Cotter and Goldstein, 1987; MacEwen
et al, 1987; Rosales et al, 1988; Postorino et al, 1989;
Rogers, 1989; Greenlee et al, 1990; Rosenthal, 1990;
Rosenthal and MacEwen, 1990; Klein, 1991; Ogilvie et al,
1991; Price et al, 1991; Stone et al, 1991; Hahn et al,
1992; MacEwen et al, 1992; Novotney et al, 1992; Keller
et al, 1993; Vail, 1993; Dobson and Gorman, 1994;
Matherne et al, 1994; Moore et al, 1994; Ruslander et al,
1994), but little progress has been made in the overall
survival of dogs with this common malignancy. Novel
approaches, including whole body hyperthermia, halfbody radiation therapy (Laing et al, 1989), continuous low
dose chemotherapy (Rosenthal, 1990; Ogilvie et al, 1991),
bone marrow transplantation (Rosenthal, 1990) and
nutritional intervention (Williams, 1988) have been
attempted, but case accessions have been quite small in
most trials.
In retrospect, it is disappointing that evaluation of
CL/MAb 231 by independent investigators was not
completed prior to its commercial release. Questions of
binding sensitivity and specificity as well as retention of
efficacy with continued passage remained unanswered
when production was discontinued, presumably for
financial considerations.
Anecdotally, during the last 34 years I have
personally treated more than 1900 dogs with intermediate
or high grade multicentric lymphoma (stages III-V) using
various combination chemotherapy protocols. Only 18
dogs have been cured, i.e., survived longer than three
years and died free of any signs of lymphoma. All but two
of those dogs never relapsed after the initial induction
chemotherapy. Interestingly, seven of the 18 dogs were
treated with CL/MAb 231 and five dogs received either
Freund's complete adjuvant or autogenous tumor vaccine
injections.
Unfortunately, the search for magic potions (drugs)
has been surprisingly unfruitful over the last three decades.
The documented success of therapeutic monoclonal
antibodies for human non-Hodgkins lymphoma, clearly
highlights the opportunity that was missed by veterinary
oncologists. It is my hope that the new generation of
veterinary oncologists will look again at immune targeting
and immunomodulation as possible paths toward cure of
this devastating cancer.

References
Benjamini E, Scibienski RJ (1974) Immunochemical approaches
to immunotherapy. Proceedings XI International Cancer
Congress 1, 327-332.
Benjamini E, Theilen GH, Torten J, Fong S, Crow SE, Henness
AM (1976) The use of tumor vaccines in immunotherapy of
canine lymphosarcoma. Ann NY Acad Sci 277, 305-312.
Brick J0, Roenigk WS, and Wilson GP (1968) Chemotherapy of
malignant lymphoma in dogs and cats. J Am Vet Med Assoc
1153, 47-52.

185

Crow: Chemoimmunotherapy for canine lymphoma: tumor vaccines and monoclonal antibodies
Laing EJ, Fitzpatrick PJ, Binnington AG, Norris AM, Mosseri A,
Rider WD, Binnington AG, Baur A, Valli VE (1989) Halfbody radiotherapy in the treatment of canine lymphoma. J
Vet Intern Med 3, 102-108.
MacEwen EG, Brown NO, Patnaik AK, Hayes AA, Passe S
(1981) Cyclic combination chemotherapy of canine
lymphosarcoma. J Am Vet Med Assoc 178, 1178-1181.
MacEwen EG, Hayes AA, Matus RE, Kurzman I (1987)
Evaluation of some prognostic factors for advanced
multicentric lymphosarcoma in the dog: 147 cases (19781981). J Am Vet Med Assoc 190, 564-568.
MacEwen EG, Rosenthal RC, Fox LE, Loar AS, Kurzman ID
(1992) Evaluation of L-asparaginase: polyethylene glycol
conjugate versus native L-asparaginase combined with
chemotherapy: a randomized double-blind study in canine
lymphoma. J Vet Intern Med 6, 230-234.
Madewell, BR (1972) Chemotherapy for canine lymphosarcoma.
Am J Vet Res 36, 1525-1528.
Marcus R (2005) Use of 90Y-ibritumomab tiuxetan in nonHodgkin's lymphoma. Semin Oncol 32 (suppl), 36-43.
Matherne CM, Satterfield WC, Gasparini A, Tonetti M, Astroff
AB, Schmidt RD, Rowe LD, DeLoach JR (1994) Clinical
efficacy and toxicity of doxorubicin encapsulated in
glutaraldehyde-treated erythrocytes administered to dogs
with lymphosarcoma. Am J Vet Res 55, 847-853.
Moore AS, Ogilvie GK, Ruslander D, Rand WS, Cotter SM,
Getzy DM, LHeureux DA, Dennis RA (1994) Evaluation of
mitoxantrone for the treatment of lymphoma in dogs. J Am
Vet Med Assoc 205, 1903-1905.
Novotney CA, Page RL, Macy DW, Dewhirst MA, Ogilvie GK,
Withrow SJ, McEntee MC, Heidner GL, Allen SA, Thrall
DE (1992) Phase I evaluation of doxorubicin and wholebody hyperthermia in dogs with lymphoma. J Vet Intern
Med 6, 245-249.
Ogilvie GK, Vail DM, Klein MK, Powers BE, Dickinson K
(1991) Weekly administration of low-dose doxorubicin for
treatment of malignant lymphoma in dogs. J Am Vet Med
Assoc 198, 1762-1764.
Postorino NC, Susaneck SJ, Withrow SJ, Macy DW, Harris C
(1989) Single agent therapy with Adriamycin for canine
lymphosarcoma. J Am Anim Hosp Assoc 25, 221-225.
Prager MD, Baechtel FS (1973) Methods for modification of
cancer cells to enhance their antigenicity. Methods Cancer
Res 9, 339-400.
Price GS, Page RL, Fischer BM, Levine JF, Gerig TM (1991)
Efficacy and toxicity of doxorubicin/cyclophosphamide
maintenance
therapy in dogs with
multicentric
lymphosarcoma. J Vet Intern Med 5, 259-262.
Rogers KS (1989) L-asparaginase for treatment of lymphoid
neoplasia in dogs. J Am Vet Med Assoc 194, 1626-1630.
Rosales C, Jeglum KA, Obrocka M, Steplewski Z (1988)
Cytolytic activity of murine anti-dog lymphoma monoclonal
antibodies with canine effector cells and complement. Cell
Immunol 115, 420-28.
Rosenberg MP, Matus RE, Patnaik AK (1991) Prognostic factors
in dogs with lymphoma and associated hypercalcemia. J Vet
Intern Med 5, 268-271.
Rosenthal RC (1990) The treatment of multicentric canine
lymphoma. Vet Clin North Am: Small Anim Pract 20,
1093-1104.
Rosenthal RC, MacEwen EG (1990) Treatment of lymphoma in
dogs. J Am Vet Med Assoc 196, 774-781.
Ruslander D, Moore AS, Gliatto JM, LHeureux D, Cotter SM
(1994) Cytosine arabinoside as a single agent for the
induction of remission in canine lymphoma. J Vet Intern
Med 8, 299-301.

Schwartz SN (1988) Spontaneous regression of lymphosarcoma

in a dog. J Am Vet Med Assoc 192, 222-224.
Sjogren HO, Hellstrom I, Bansal SC, Hellsrom KE (1971)
Suggestive evidence that the blocking antibodies of tumor
bearing individuals may be antigen-antibody complexes.
Proc Natl Acad Sci 68, 1372-1375.
Smith RT, Adler WH (1970) Humoral tumor immunity. N Engl
J Med 282, 1320-2322.
Squire RA, Bush M, Melby EC, Neeley LM, Yarbrough B
(1973) Clinical and pathologic study of canine lymphoma:
clinical staging, cell classification, and therapy. J Natl
Cancer Inst 51, 565-574.
Steplewski Z, Jeglum KA, Rosales C, Weintraub N (1987)
Canine lymphoma-associated antigens defined by murine
monoclonal antibodies. Cancer Immunol Immunother 24,
197-201.
Stone MS, Goldstein MA, Cotter SM (1991) Comparison of two
protocols for induction of remission in dogs with lymphoma.
J Am Anim Hosp Assoc 27, 315-321.
Teske E, van Heerde P, Rutteman GR, Kurzman ID, Moore PF,
MacEwen EG (1994) Prognostic factors for treatment of
malignant lymphoma in dogs. J Am Vet Med Assoc 205,
1722-1728.
Theilen
GH,
Worley
M,
Benjamini,
E
(1977)
Chemoimmunotherapy for canine lymphosarcoma. J Am
Vet Med Assoc 170, 607-610.
Thompson K, Harris M, Benjamini E, Mitchell G, Nobel M
(1972) Cellular and humoral immunity-a distinction in
antigenic recognition. Nature 238, 20-21.
Vail DM (1993) Recent advances in chemotherapy for
lymphoma of dogs and cats. Compend Contin Educ Pract
Vet 15, 1031-1037.
Weller RE, Theilen GH, Madewell BR, Crow SE, Benjamini E,
Villalobos A (1980) Chemoimmunotherapy for canine
lymphosarcoma: a prospective evaluation of specific and
nonspecific immunomodulation. Am J Vet Res 41, 516-521.
Williams JH (1988) The use of gamma linolenic acid, linoleic
acid and natural vitamin E for the treatment of multicentric
lymphoma in two dogs. J South African Vet Assoc 59, 141144.
Witney, R, Levy J, Smith AG (1974) Influence of tumor size and
surgical resection on cell mediated immunity in mice. J Natl
Cancer Inst 53, 111-116.
Witzig TE (2006) Radioimmunotherapy for B-cell non-Hodgkin
lymphoma. Best Pract Res Clin Haematol 19, 655-68.

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