Beruflich Dokumente
Kultur Dokumente
1,617-623, 1977
Transfer Factor:
a Potential Agent for Immunotherapy of Cancer
C. RICHARD MEIER, M . D .
a n d ALBERT F. L O B u G L I O , M , D .
Divbion of Hematology and Oncology, Department of Medicine, The Ohio State University,
Columbus. Ohio. U.S.A.
phocytes in the rejection of experimental tumor allografts was demonstrated by Mitchison [6]. Indeed. in
another important series of animal experiments, the
allograft reaction was shown to closely resemble tuberculin and contact hypersensitivity in its timing,
histological appearance, and independence of antibody [7]. Subsequently, a series of studies [8, 9] revealed the existence of 2 or more functionally different lymphocyte subpopulations. B (bursa-equivalent
or bone marrow-derived) cells and T (thymus-dependent) cells. It is now known that B lymphocytes are
involved in the humoral (antibody) immune response, while T cells are responsible for skin hypersensitivity reactions and graft rejection. Additionally,
T cells have the capacity to destroy target cells (tumor
cells) by several mechanisms involving both specific
sensitization as well as mitogen-dependent cytotoxicity [10]. In the light of these findings, a significant observation was that humans with advanced malignancies often have decreased or absent cutaneous
hypersensitivity reactions [11. 12], and that vigorous
skin reactivity may be correlated with a better prognosis relative to patients with the same malignancy
who are skin test negative [13, 14]. Consequently, an
effective immunotherapeutic agent might be expected
to reinstitute skin reactivity while enhancing the patient's lymphocyte reactivity against his malignant
cells. In this context, the observations of Lawrence
gained intriguing perspective and stimulated considerable research activity.
The concept of immunotherapy for cancer has intrigued clinicians for a long time. An ideal immunotherapy agent, besides being effective against cancer.
is one that "should be nonantigenic, nontoxic and
could be given in large doses repeatedly." Indeed.
Lawrence believed that these last criteria were met by
transfer factor [1]. In the early 1950's he originally
described the transfer of skin reactivity to tuberculin
[2, 3] and streptococcal antigen [2] to previously nonreactive subjects by administration of a leukocyte extract obtained from peripheral leukocytes of reactive
individuals. He named the responsible agent transfer
factor (TF).
A latency period of several years followed these reports. That tuberculin skin reactions were different
f r o m antibody-mediated skin reactions [4] and resembled experimental contact hypersensitivity [5]
had been known for a long time, but these findings
gained perspective only after the essential role of lyre-
General Characteristics o f T F
618
design and interpretation of new and old TF experimelats. However, most information regarding the
properties of TF has come from attempts to transfer
bacterial or fungal hypersensitivity in man. The active component(s) of TF have a low molecular
weight, since TF is dialyzable and shows delayed elution on Sephadex G-25 chromatography [17, 18]. In
the lyophilized state TF remains active for years and
DNAse, RNAse, and trypsin do not destroy its activity [2, 19]. Evidence indicates that it contains a nucleotide peptide hybrid [20] and that hypoxanthine is
one component [21]. TF preparations are not
immunogenic by themselves and do not contain histocompatibiiity antigen [19]. Hepatitis infection associated with TF therapy is rare, but pain at the site of
injection and fever have been reported to be common
[22]. TF activity is destroyed by heating at 56 ~ for 30
minutes [23]. Table 1 summarizes the procedures usually employed in transfer factor studies in humans
[241.
Therapy of Immunodeficiency States and Infections
with Transfer Factor
Generally, TF therapy has been tried in two circumstances. TF has been used as an adjuvant to conventional therapy, i.e., surgery, radiotherapy a n d / o r
chemotherapy, at a period of presumably low tumor
cell load. The other circumstance has involved patients with widely metastatic disease.
Table 1. Design of transfer factor studies in man.
Donor identification
Donation of leukocytes (phlebotomy or blood cell
separator)
Leukocyte disruption (freeze thaw or sonication)
Harvest of low molecular weight components (dialysis,
Ultrafiltration, or chromatography)
Volume reduction (lyophilization)
Administration (intradermal, subcutaneous, or
intramuscular injection)
Documentation of effects (skin tests, in vitro assays,
clinical response)
Most of the trials of TF adjuvant therapy have involved patients with osteosarcoma. Levin et al. [36]
reported that all of 7 patients responded to administration of TF as an adjuvant to surgical resection during a follow-up period of from 7 to 28 months. In our
series, 3 out of 5 osteosarcoma patients have done
well for 7, 8, and 17 months after surgery combined
with adjuvant TF therapy, while the other 2 patients
relapsed 4 and 12 months, respectively, after entering
the program. Another 2 patients with metastatic
osteosarcoma achieved complete remission on combination chemotherapy, and remain disease free on
TF therapy alone for 11 and 28 months, respectively.
In another study of osteosarcoma, TF was compared
to adjuvant chemotherapy after surgery for clinically
localized disease [37]. In a preliminary report, 4 of 8
TF-treated patients and 4 of 18 chemotherapy patients had relapsed. The cumulative incidence of metastases was 8.7 for the TF group and 5.1 for the
chemotherapy group per 100 patient-months.
Bearden et al. [38] reported 3 out of 6 patients on adjuvant TF therapy combined with adjuvant chemotherapy free of recurrence for 7, 11, and 17+ months;
the others had relapsed at 4, 6, and 14 months after
amputation. It appeared that the patients who relapsed had been started on the adjuvant therapy relatively late (i.e., more than 2 months after surgery). In
the treatment of metastatic osteogenic sarcoma with
TF, Levin et al. [36] reported 1 out of 6 responses,
and LoBuglio et al. [39] reported 1 patient with stationary disease for 6 months.
Regarding other metastatic cancers, patients with
malignant melanoma have been most often treated
with TF. Cumulative results from various series [22,
40-47] indicate an overall response rate of 16 out of
64 patients. Obviously, however, not all patients were
treated in the same fashion. For example, Krementz
et al. [40] transfused viable lymphocytes rather than
TF in most of their patients, and some patients from
other series had additional radiotherapy [43] or BCG
immunization [47] along with TF. "Response" was
defined variably or not at all, and was itself reported
as quite variable in duration and degree. Other problems concerning the design of such studies in general
are discussed below, but especially in melanoma patients a spontaneous coincidental regression is difficult to rule out [47, 48].
TF therapy for metastatic breast cancer has been
generally unsuccessful, with only 2 of 12 patients responding in 3 reports [42, 45, 49]. Goldenberg et al.
[50, 51] have reported tumor regression or temporary
arrest in 2 of 3 patients with nasopharyngeal carcinoma treated with TF from donors assumed to have
a history of infection with Ebstein-Barr virus. Silva et
al. [45] reported 1 patient with a 10-month remission
after TF therapy for metastatic vulvar carcinoma, but
C.R. Meier and A.F. LoBuglio: Immunotherapy of Cancer with Transfer Factor
no responses were seen in patients with ovarian cancer, lung carcinoma, or thymoma (1 each). Quick et
al. [52] reported 2 pediatric patients with chronically
recurrent obstructing laryngeal papillomatosis. After
treatment with TF prepared from family members or
from a papillomatosis patient in remission, the intervals between required surgical excisions appeared to
be longer.
Measurable Effects of Transfer Factor Treatment
619
Le facteur de transfert (TF) est un extrait de leucocytes humains. I1 a 6t6 d6montr6 qu'il transf~re
l'homme anergique une capacit6 de r6action cutan6e
sp6cifique et qu'il augmente la r6ponse des tests
d'activit6 lymphocytaire in vitro. Le TF a 6t6 utilis6,
titre exp6rimental, pour l'immunoth6rapie anticanc6reuse. Dans plusieurs cas, l'administration de
TF a 6t6 suivie de r6gression de tumeurs, de stabilisation temporaire, et l'on a 6galement observ6 qu'il
6tait possible, sous TF, de r6duire les autres besoins
thdrapeutiques. Le TF est donc peut-6tre valable en
tant que th6rapeutique adjuvante de certains cancers.
Cependant, la plupart des travaux publi6s sont des
6tudes non contrSldes, et il n'existe aucun accord
quant aux crit6res de d6finition du donneur de TF. II
sera impossible de tirer des conclusions quant/t la valeur des traitements par TF dans le cancer ou d'autres
maladies, aussi longtemps que des 6tudes contrSl6es
n'auront pas 6t6 rdalis6es et que les caract~res des
donneurs de TF ne seront pas ddfinis.
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620
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C.R. Meier and A.F. LoBuglio: Immunotherapy of Cancer with Transfer Factor
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