NZ624994B2 - Immunogenic treatment of cancer - Google Patents
Immunogenic treatment of cancer Download PDFInfo
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- NZ624994B2 NZ624994B2 NZ624994A NZ62499412A NZ624994B2 NZ 624994 B2 NZ624994 B2 NZ 624994B2 NZ 624994 A NZ624994 A NZ 624994A NZ 62499412 A NZ62499412 A NZ 62499412A NZ 624994 B2 NZ624994 B2 NZ 624994B2
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- cancer
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- cell death
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Abstract
Disclosed is the use of an immunomodulator comprising a non-pathogenic heat-killed whole cell Mycobacterium in the preparation of a medicament for use in the treatment and/or control of a neoplastic disease in a patient intended to undergo immunogenic cell death therapy simultaneously, separately or sequentially with administration of the immunomodulator, wherein the Mycobacterium is M. obuense; wherein said immunogenic cell death therapy is selected from microwave irradiation, targeted radiotherapy, embolisation, cryotherapy, ultrasound, high intensity focused ultrasound, cyberknife, hyperthermia, radiofrequency ablation, cryoablation, electrotome heating, hot water injection, alcohol injection, embolization, radiation exposure, photodynamic therapy, laser beam irradiation, and combinations thereof; wherein said immunogenic cell death therapy is to be carried out at a sub-optimal level that is not intended to fully remove or eradicate the tumour of said neoplastic disease. sequentially with administration of the immunomodulator, wherein the Mycobacterium is M. obuense; wherein said immunogenic cell death therapy is selected from microwave irradiation, targeted radiotherapy, embolisation, cryotherapy, ultrasound, high intensity focused ultrasound, cyberknife, hyperthermia, radiofrequency ablation, cryoablation, electrotome heating, hot water injection, alcohol injection, embolization, radiation exposure, photodynamic therapy, laser beam irradiation, and combinations thereof; wherein said immunogenic cell death therapy is to be carried out at a sub-optimal level that is not intended to fully remove or eradicate the tumour of said neoplastic disease.
Description
IMMUNOGENIC TREATMENT OF CANCER
FIELD OF THE INVENTION
The present invention relates to the field of cancer therapy. In particular, the
present invention relates to a method of treating the development of tumours or
metastases in a subject and to an immunomodulator for use in such therapy, in
combination with a procedure which results in localized tumour cell damage or
immunological cell death.
OUND OF THE INVENTION
In recent years there has been a growing realization that immune responses play a
central role in cancer y by ating many tumours at a very early stage and
keeping those that avoid total elimination in a state of equilibrium, sometimes for
many years (Dunn et al, Annu Rev Immunol 2004; -360). The eventual
escape from this equilibrium phase with clinical manifestation of the disease is
associated with dysregulated immune responses, sting, for example, as
chronic inflammation or immunesuppression. The strong and increasing ce
that the immune system is critically involved in the development, structural nature
and progression of cancer has led to renewed interest in immunotherapeutic
strategies for treatment of this class of diseases. To date, most attempts to develop
such gies have been based on the use of antigens derived from the patient's
own tumour or from tumour cell lines and the transfer of ex-vivo expanded
populations of tumour antigen-specific cytotoxic cells and antigen-presenting cells.
Cancer has been associated with inflammation since 1863, when Rudolf Virchow
discovered leucocytes in neoplastic tissues and so made the first connection
between inflammation and cancer (Balkwill et al, Lancet 2001 ; 357:539-545). Since
then, chronic inflammation has been deemed to be a risk factor for cancer. These
reports demonstrate that an matory environment supports tumour
development and is consistent with that observed at tumour sites. r, the
relationship of cancer with inflammation is not limited to the onset of the disease
due to c inflammation. Schwartsburd (Cancer and asis reviews 2003;
22:95-102) proposed that chronic inflammation occurs due to tumour environment
stress and that this generates a shield from the immune . It has been
recently demonstrated that the tumour microenvironment resembles an
inflammation site, with significant support for tumour progression, through
ines, cytokines, lymphocytes and macrophages which contribute to both the
neovascularisation and vasal dilation for increased blood flow, the
immunosuppression associated with the malignant disease, and the establishment
of tumour metastasis. Furthermore, this inflammation-site tumour-generated
microenvironment, apart from its significant role in protection from the immune
system and ion of cancer progression, has an adverse effect on the s
of current cancer treatments. Indeed, it has been found that the inflammatory
response in cancer can compromise the pharmacodynamics of chemotherapeutic
agents (Slaviero et al, Lancet Oncol 2003; 4:224-32).
Moreover, metastatic cancer cells leave the tumour as microcolonies, containing
lymphocytes and ets as well as tumour cells. mation continues to play a
role at metastatic sites by creating a cytokine milieu conducive to tumour .
Immune tasis consists of a tightly regulated interplay of pro- and anti
inflammatory signals. For example, loss of the anti-inflammatory signals leads to
chronic inflammation and proliferative signalling. Interestingly, nes that both
promote and suppress proliferation of the tumour cells are ed at the tumour
site. As in the case of cancer tion, it is the imbalance between the effects of
these various processes that results in tumour promotion.
It is believed that, to treat cancer, the most effective type of immune response is of
a Type 1, which favours the induction of CD4+ Th1 cellular responses, and of
CD8+ CTL responses. In the context of cancer vaccines, many immune stimulants
are used, which promote the development of Th1 responses and are thought to
inhibit the production of a Th2 response.
To date, a major barrier to attempts to develop effective immunotherapy for cancer
has been an inability to break immunosuppression at the cancer site and restore
normal networks of immune vity. The physiological approach of
immunotherapy is to normalize the immune reactivity so that the endogenous
tumour antigens would be again recognized and effective cytolytic ses would
be developed against cells bearing these antigens.
Anti-cancer immune responses accompanying the action of chemo- and
radiotherapy have been recently reviewed and show that such responses are
critical to therapeutic success by eliminating al cancer cells and maintaining
micrometastases in a state of dormancy (Zitvogel et al, J Clin Invest
2008;1 18:1991-2001). However, this reference makes it clear that there is no
simple immunotherapeutic strategy available for consistently enhancing such
immune responses.
There is evidence that therapeutic procedures that induce certain forms of
immunogenic cancer cell death also lead to e of tumour antigens. There are
three main types of cell death ere et al, Cell Death Differ 2008; 15:3-12):
apoptosis (type 1), autophagy (type 2) and necrosis (type 3). Apoptosis, or
programmed cell death, is a common and regular occurring phenomenon essential
for tissue remodelling, especially in utero but also ex utero. It is characterized by
DNA fragmentation in the s and sation of the cytoplasm to form
'apoptotic bodies' which are engulfed and digested by phagocytic cells. In
autophagy, cell organelles and cytoplasm are sequestered in vacuoles which are
extruded from the cell. Although this provides a means of survival for cells in
adverse nutritional conditions or other stressful situations, excess autophagy
results in cell death. Necrosis is a 'cruder' process characterized by damage to
intracellular organelles and cell swelling, resulting in rupture of the cell membrane
and release of ellular material.
It has widely been held that apoptosis is immunologically 'silent', as would be
expected from its physiological role and by the finding that local mation is
suppressed by the release of nflammatory mediators. More recently it has
been suggested that there are different forms of apoptosis and some are
immunogenic (Zitvogel et al, Adv Immunol 2004; 84: 131-179). The relationship of
autophagy to genicity is poorly understood but is nly releases
many antigens, although in progressive cancers, such necrosis might also enhance
the chronic inflammation that s tumour growth (Vakkila et al, Nat Rev
Immunol 2004; 4 : 641-648; Zeh et al, J Immunother 2005; 28:1-9). In this sense, a
cancer resembles a chronically inflamed wound that does not heal (Dvorak. N Engl
J Med 1986; 315:1650-1659).
Necrosis has been principally classified as immunogenic cell death. A limited
number of studies indicate that procedures inducing immunogenic cell death
release mediators and tumour antigens that are able to both induce immune
responses, including activation of cytotoxic CD8+ T cells and NK cells and act as
targets, including rendering antigens accessible to Dendritic Cells (DC), able in
principle to create an in vivo DC vaccine.
It is more useful to categorize cell death into immunogenic and non-immunogenic
forms, ective of the precise mechanism of such cell death. In a therapeutic
setting with restoration of beneficial immune regulation, antigens ed by
immunogenic cell death would then be able to elicit effective umour immune
responses, particularly if they are e in the presence of Danger-Associated (or
Damage-Associated) Molecular Pattern (DAMP) e et al., N . Eng. J . Med.
2004; 350: 4 ) .
s have been made in the art to e ed ablative and
chemotherapies for the treatment of tumours. WO2000064476 and
US200501 87207 disclose the use of an immunoadjuvant in combination with
photodynamic therapy for the treatment of metastatic tumours. These documents
disclose that the immunoadjuvant comprises mycobacterial cell wall skeletons and
deO-acylated lipid A and is administered by injection into the tumour. Castano et
al (Nat Rev Cancers 2006; , Korbelik et al (J Photochem and Photobiol 1998;
44:151) and ik et al (J Photochem and Photobiol, 2001 ; 73:403) also disclose
the treatment of tumours using a combination of photodynamic therapy and the
administration of mycobacterial cell wall extract as an immunoadjuvant.
Mycobacterial cell walls contain compounds such as trehalose dimycolate and
muramyl dipeptide which are known immunostimulators. The mycobacterial cell
wall extracts used in the prior art combination therapies also elicit pro-inflammatory
nes, reactive nitrogen s and recruit leukocytes which are associated
with pathology including weight loss due to TNF-a mediated cachexia, with
associated lipidemia, hypoglycaemia and peritonitis with ischemic and hemorrhagic
lesions in the Gl tract. The prior art combination therapies may therefore
exacerbate the inflammatory response and have severe side-effects.
SUMMARY OF THE INVENTION
The t invention provides a safe, olerated and effective method for
treating cancer by employing techniques leading to immunogenic cell death which
act synergistically with immunotherapy. The present invention provides a
combination of an genic cell death therapy applied to a tumour er with
a specific type of immunotherapy. The inventors have found that the combination of
both therapies is synergistic beyond simple additive effects of each therapy used
individually.
In a first aspect, the invention provides an immunomodulator for use in the treatment
and/or control of a stic e in a patient intended to undergo immunogenic
cell death therapy simultaneously, separately or sequentially with administration of
the immunomodulator.
In another aspect, the invention provides an immunomodulator comprising a non-
pathogenic heat-killed whole cell Mycobacterium for use in the treatment and/or
control of a neoplastic disease in a patient ed to undergo immunogenic cell
death therapy simultaneously, separately or sequentially with administration of the
immunomodulator, wherein the Mycobacterium is selected from M. vaccae, M.
obuense and combinations thereof; wherein said immunogenic cell death y is
selected from microwave irradiation, targeted radiotherapy, embolisation,
cryotherapy, ultrasound, high intensity focused ound, cyberknife, hyperthermia,
radiofrequency ablation, cryoablation, electrotome heating, hot water injection,
alcohol injection, embolization, radiation exposure, photodynamic therapy, laser
beam irradiation, and ations thereof; wherein said genic cell death
therapy is to be carried out at a sub-optimal level that is not intended to fully remove
or eradicate the tumour of said neoplastic disease.
In r aspect, the invention provides the use of an immunomodulator comprising a
thogenic heat-killed whole cell Mycobacterium in the preparation of a medicament for
use in the treatment and/or control of a neoplastic disease in a patient intended to undergo
immunogenic cell death y simultaneously, separately or sequentially with
administration of the immunomodulator, wherein the Mycobacterium is selected from M.
e; wherein said immunogenic cell death therapy is selected from microwave
ation, targeted radiotherapy, embolisation, cryotherapy, ultrasound, high intensity
focused ultrasound, cyberknife, hyperthermia, radiofrequency ablation, cryoablation,
electrotome heating, hot water injection, alcohol injection, embolization, radiation exposure,
photodynamic therapy, laser beam ation, and combinations thereof; wherein said
immunogenic cell death therapy is to be carried out at a sub-optimal level that is not
intended to fully remove or eradicate the tumour of said neoplastic e.
In a second aspect, the ion is a method of treating, inhibiting or controlling the
development of a tumour in a subject comprising undertaking immunogenic cell
death therapy in a subject and the simultaneously, separate or sequential
administration to the subject of an effective amount of an immunomodulator.
Description of the Drawings
The invention is described with nce to the following drawing, in which:
Figure 1 shows the results of a study on the effect of administering an
immunomodulator (heat-killed Mycobacterium obuense; 1 ) to an animal
undergoing ablative irradiation treatment for cancer. The results show that the
combination is synergistically better than ent by irradiation alone.
[Text continued on page 6]
Detailed Description of the Invention
An immunomodulator, as defined according to the present invention, is a
component which stimulates Type 1 response and down regulates Th2 responses
and which restores the healthy balance of the immune system, through
immunoregulation.
The present ion requires immunogenic cell death therapy. This therapy
s in the ion of tumour genic cell death, including apoptosis (type
1), autophagy (type 2) and necrosis (type 3), whereupon there is a release of
tumour antigens that are able to both induce immune responses, including
activation of xic CD8+ T cells and NK cells and to act as targets, including
rendering antigens ible to Dendritic Cells. The procedures which cause
immunogenic cell death of the tumour, are highlighted below.
In the context of the present invention, "immunogenic tumour cell death therapy"
refers to the ability to physically induce damage in a tumour or tumour cells, so that
the cells release antigens which are ed by the immune system to recognize
and target the tumour. The term includes ablative therapies. The release of
tumour antigens can be shown by observing an increase in, for example, recall
ses and cytotoxic T cell responses.
The immunogenic cell death therapy may be carried out at sub-optimal levels, i.e.
non-curative therapy such that it is not intended to fully remove or eradicate the
tumour, but nevertheless results in some tumour cells or tissue becoming necrotic.
The skilled person will appreciate the extent of therapy required in order to achieve
this, depending on the technique used, age of the patient, status of the disease and
particularly size and location of tumour or metastases.
aneous stration, as defined herein, includes the administration of the
immunomodulator and cell death therapy procedure within about 2 hours or about 1
hour or less of each other, even more preferably at the same time.
Separate administration, as defined herein, includes the administration of the
immunomodulator and cell death therapy procedure more than several weeks,
several days, about 12 hours, or about 8 hours, or about 6 hours or about 4 hours
or about 2 hours apart.
Sequential administration, as defined herein, includes the administration of the
immunomodulator and cell death therapy procedure in multiple aliquots and/or
doses and/or on separate occasions. ably the immunomodulator is
administered before and continued to be administered to the patient after the cell
death therapy procedure occurs. More preferably, the immunomodulator is
continued to be applied to the patient after treatment for regression of the tumour.
In one aspect of the present invention the modulator comprises heat-killed
Mycobacterium. Preferred mycobacterial species for use in the present invention
include M. vaccae, M. thermoresistibile, M. flavescens, M. duvalii, M. phlei, M.
obuense, M. rtuitum, M. sphagni, M. nse, M. rhodesiae, M. neoaurum,
M. chubuense, M. nse, M. komossense, M. aurum, M. w, M. tuberculosis, M.
microti; M. africanum; M. ii, M. marinum; M. simiae; M. gastri; M.
nonchromogenicum; M. terrae; M. triviale; M. gordonae; M. scrofulaceum; M.
paraffinicum; M. intracellulare; M. avium; M. xenopi; M. ulcerans; M. diernhoferi, M.
smegmatis; M. thamnopheos; M. flavescens; M. fortuitum; M. peregrinum; M.
chelonei; M. paratuberculosis; M. leprae; M. murium and combinations
Preferably, the heat-killed Mycobacterium is non-pathogenic. The non-pathogenic
heat-killed Mycobacterium is selected from M. vaccae, M. obuense, M.
parafortuitum, M. aurum, M. w, M. phlei and combinations thereof. More preferably
the non-pathogenic heat-killed Mycobacterium is a rough variant. The amount of
immunomodulator stered to the patient is sufficient to elicit a protective
immune response in the patient such that the patient's immune system is able to
mount an effective immune response to tumour cell antigens ing tumour cell
ablation, or immunogenic cell death. In certain embodiments of the invention, it is
preferable that particular a dosage of immunomodulator be administered to a
t. Thus, in certain embodiments of the invention, there is provided a
nment means comprising the effective amount of heat-killed Mycobacterium
for use in the present invention, which typically may be from 103 to 1011 organisms,
preferably from 104 to 1010 organisms, more ably from 106 to 1010 organisms,
and even more preferably from 10 to 10 organisms. The effective amount of heatkilled
Mycobacterium for use in the present invention may be from 103 to 1011
organisms, preferably from 104 to 1010 organisms, more preferably from 106 to 1010
sms, and even more preferably from 106 to 109 sms. Most preferably
the amount of heat-killed Mycobacterium for use in the present ion is from
107 to 109 cells or organisms. Typically, the composition according to the present
ion may be administered at a dose of from 108 to 109 cells for human and
animal use. Alternatively the dose is from 0.01 mg to 1 mg or 0.1 mg to 1mg
organisms presented as either a suspension or dry preparation.
M. vaccae has the ability to modulate immune responses. Its Type 1 adjuvant
property is unaffected by illing, whereas other cteria, such as BCG,
have little Type 1 adjuvant effect when dead. M. vaccae also downregulates pre
existing Th2 responses in a manner that appears to be independent of its ability to
e Type-1 responses. This effect has now been attributed to induction of
CD4+CD45RB |0W regulatory T-cells that in an experimental model of ary
allergic inflammation can suppress allergic inflammation and airway hyper-reactivity
when transferred to allergic recipients. M. obuense also shows immunomodulatory
effects.
Unlike agents that target single cytokine mediators, M. vaccae has a wider effect
through its y to reduce several Th2 cytokines, including IL-4, IL-5 and IL-13,
via immunoregulatory mechanisms including induction of regulatory T-cells that
down-regulate Th2 via a mechanism involving IL-10 and Transforming growth
factor GF)- .
M. vaccae and M. obuense induce a complex immune response in the host.
Treatment with these preparations will stimulate innate and type-1 immunity (Th1
and CD8+ CTLs) akin to what has been observed with ent with other
mycobacterial preparations (for example live attenuated BCG and mycobacterial
cell wall extracts). However, a significant additional benefit of treatment with
M. vaccae and M. obuense, is the tion of the immune response through the
induction of regulatory cells (T-regulatory and DC with regulatory phenotype) which
control and modulate prolonged and over-exuberant immune reactions (for
example, following tumour on). Tight control of immune reactions through
regulation not only limits tissue ogy but also ensures a quick return to
energy ent steady state immune equilibrium.
The present invention may be used to treat, l or inhibit a neoplastic disease.
Cancers that may be treated according to the invention include but are not limited
to cells or neoplasms of the bladder, blood, bone, bone marrow, brain, breast,
colon, esophagus, gastrointestines, gum, head, kidney, liver, lung, nasopharynx,
neck, ovary, te, skin, stomach, testis, tongue, or uterus. In addition, the
cancer may specifically be of the following histological type, though it is not d
to the following: neoplasm, malignant; carcinoma; carcinoma, undifferentiated; giant
and spindle cell carcinoma; small cell carcinoma; papillary carcinoma; squamous
cell carcinoma; lymphoepithelial carcinoma; basal cell carcinoma; pilomatrix
carcinoma; transitional cell carcinoma; papillary transitional cell carcinoma;
adenocarcinoma; gastrinoma, ant; cholangiocarcinoma; hepatocellular
oma; combined cellular oma and cholangiocarcinoma;
trabecular adenocarcinoma; adenoid cystic carcinoma; adenocarcinoma in
adenomatous polyp; adenocarcinoma, familial polyposis coli; solid carcinoma;
carcinoid tumour, malignant; bronchiolo-alveolar adenocarcinoma; papillary
adenocarcinoma; chromophobe carcinoma; hil carcinoma; oxyphilic
adenocarcinoma; basophil carcinoma; clear cell adenocarcinoma; ar cell
carcinoma; follicular adenocarcinoma; papillary and follicular adenocarcinoma;
nonencapsulating sclerosing carcinoma; adrenal cortical carcinoma; endometroid
carcinoma; skin appendage carcinoma; apocrine adenocarcinoma; sebaceous
adenocarcinoma; ceruminous adenocarcinoma; mucoepidermoid carcinoma;
cystadenocarcinoma; papillary cystadenocarcinoma; papillary serous
cystadenocarcinoma; mucinous cystadenocarcinoma; mucinous adenocarcinoma;
signet ring cell carcinoma; infiltrating duct carcinoma; medullary carcinoma; lobular
carcinoma; inflammatory carcinoma; Paget's disease, mammary; acinar cell
carcinoma; adenosquamous carcinoma; adenocarcinoma with squamous
metaplasia; thymoma, malignant; ovarian l tumour, malignant; thecoma,
malignant; granulosa cell , malignant; androblastoma, malignant; Sertoli cell
carcinoma; Leydig cell tumour, malignant; lipid cell tumour, malignant;
paraganglioma, malignant; mammary paraganglioma, malignant;
pheochromocytoma; glomangiosarcoma; malignant melanoma; otic
melanoma; superficial spreading ma; malignant melanoma in giant
pigmented nevus; epithelioid cell melanoma; blue nevus, malignant; sarcoma;
fibrosarcoma; fibrous histiocytoma, malignant; myxosarcoma; liposarcoma;
leiomyosarcoma; rhabdomyosarcoma; embryonal rhabdomyosarcoma; alveolar
rhabdomyosarcoma; stromal sarcoma; mixed tumour; Mullerian mixed tumour;
nephroblastoma; hepatoblastoma; carcinosarcoma; mesenchymoma, malignant;
Brenner tumour, ant; phyllodes tumour, malignant; synovial sarcoma;
mesothelioma, malignant; dysgerminoma; embryonal carcinoma; teratoma,
malignant; struma ovarii, ant; choriocarcinoma; mesonephroma, malignant;
hemangiosarcoma; hemangioendothelioma, malignant; Kaposi's sarcoma;
hemangiopericytoma, malignant; lymphangiosarcoma; osteosarcoma; juxtacortical
arcoma; chondrosarcoma; chondroblastoma, malignant; mesenchymal
chondrosarcoma; giant cell tumour of bone; Ewing's sarcoma; odontogenic tumor,
malignant; ameloblastic odontosarcoma; ameloblastoma, malignant; ameloblastic
fibrosarcoma; pinealoma, malignant; chordoma; glioma, malignant; ependymoma;
ytoma; protoplasmic astrocytoma; lary astrocytoma; astroblastoma;
glioblastoma; oligodendroglioma; oligodendroblastoma; primitive neuroectodermal;
llar sarcoma; ganglioneuroblastoma; neuroblastoma; retinoblastoma;
olfactory neurogenic tumour; meningioma, malignant; neurofibrosarcoma;
neurilemmoma, malignant; granular cell , malignant; ant lymphoma;
n's disease; Hodgkin's; paragranuloma; malignant lymphoma, small
lymphocytic; malignant lymphoma, large cell, diffuse; ant lymphoma,
ular; s fungoides; other specified dgkin's lymphomas; malignant
histiocytosis; multiple myeloma; mast cell sarcoma; immunoproliferative small
intestinal disease; leukemia; lymphoid leukemia; plasma cell leukemia;
erythroleukemia; sarcoma cell leukemia; myeloid leukemia; basophilic
leukemia; philic leukemia; monocytic leukemia; mast cell leukemia;
megakaryoblastic leukemia; myeloid sarcoma; and hairy cell leukemia. Preferably,
the neoplastic disease may be tumours ated with a cancer selected from
prostate cancer, liver cancer, renal cancer, lung cancer, breast cancer, colorectal
cancer, pancreatic , brain cancer, hepatocellular cancer, lymphoma,
leukaemia, gastric cancer, cervical cancer, ovarian cancer, thyroid cancer,
melanoma, head and neck cancer, skin cancer and soft tissue sarcoma and/or
other forms of carcinoma. The tumour may be metastatic or a malignant tumour.
Ablation-induced damage of the tumour is characterized for example by antigen
e, cellular debris and release of ors which give rise to a strong
immune reaction. The further on of an insult such as one delivered by the
intratumoural administration of mycobacterial cell wall extract of the prior art further
stimulates the immune system leading to additional inflammation and immune
reactivity to shared and tumour antigens. Because of its nature, this response to
the mycobacterial cell wall extract may proceed uncontrolled. Pre-treatment with
heat-killed whole cell M. vaccae and M. obuense gives rise to more complex
ty including not only the development of innate immunity and type-1
immunity, but also immunoregulation which more efficiently restores appropriate
immune functions.
The immunogenic cell death therapy is preferably carried out on metastatic cancer
cells or tissue rather than the primary tumour. Metastatic cancer cells are those
cancer cells that have spread from the primary tumours. Treatment is carried out
with the aim of g disruption to the tumours such that there is the release of
tumour antigens which can then be recognised by the immune system.
Accordingly, the treatment can be carried out at sub-lethal levels, sufficient to
induce a minimal cell damage. The metastatic cancer cells or tissue may be
present in an organ or site different to that of the primary tumour.
The metastatic cancer may be identified using techniques tional in the art,
including lab tests, x-rays, computed tomography (CT) scan, magnetic resonance
imaging (MRI) scan and position emission tomography (PET) scan, or
combinations thereof.
The treatment does not have to result in eradication, but can aim at disrupting a
tion of the cells or tissue, to trigger an immune response, e.g. the treatment
can result in necrosis of the proportion of the atic cancer cells or tissue. In
this regard, the ques may be employed under timal conditions,
requiring only to disrupt a proportion of the cells or .
Before and/or after disruption of the tumour tissue, effective amounts of the
immunomodulator, e.g. cell Mycobacterium, may be administered in multiple
(repeat) doses, for example two or more, three or more, four or more, five or more,
ten or more, or twenty or more repeat doses, at intervals of about 2 weeks, or about
4 weeks or about 8 weeks.
Alternatively, the immunogenic cell death therapy may be performed
simultaneously with the administration of the effective amounts of the
immunomodulator (e.g. whole-cell Mycobacterium).
In a further embodiment the immunogenic cell death y may be performed
after the stration of the effective amount of the immunomodulator (e.g.
whole-cell Mycobacterium).
In a further embodiment immunogenic cell death therapy may be performed or
administered after the administration of the effective amount of the
modulator (e.g. whole-cell cterium).
In a further embodiment the immunogenic cell death therapy is performed or
administered before the stration of the effective amount of the
Mycobacterium.
The immunomodulator may be administered to the patient via the parenteral, oral,
sublingual, nasal or pulmonary route. In a preferred ment, the
immunomodulator is administered via a eral route selected from
subcutaneous, intradermal, subdermal, intraperitoneal, intravenous and
intravesicular injection. More preferably, administration by the parenteral route
does not comprise umoural injection of mycobacterial cell wall t.
The immunogenic cell death therapy may comprise any means of physical
denaturation or disruption of the tumour tissue including tumour ablation. Ablation
may involve any minimally invasive technique designed to destroy malignant tissue
with minimal damage to surrounding normal tissue. These techniques have
received considerable interest in recent years because of their potential for
decreased cost, lower morbidity, and utilization in an outpatient setting.
Additionally, in contrast to al resection, tumour recurrences can be readily
treated with these newer ablative therapies. In a preferred embodiment the ablative
tumour tive therapy may be selected from microwave irradiation,
radiofrequency ablation, targeted radiotherapy, embolisation, cryotherapy,
ound, high intensity focused ultrasound, cyberknife, hermia,
cryoablation, electrotome heating, hot water injection, alcohol injection,
embolization, radiation re including Cesium-131 brachytherapy (internal
radiation y) seeds, photodynamic therapy, laser beam irradiation and
combinations thereof. However, the means of physical denaturation or disruption is
not limited to these examples, and any means that can induce immunogenic cell
death of tumour cells in a tumour tissue can be used. More preferably, two or more
kinds of ablative tumour therapies may be suitably combined. The means of
physical ration or disruption of the tumour tissue preferably s in
necrosis or apoptosis of at least a portion of the tumour cells. The means of
physical denaturation or disruption of the tumour tissue may cause sub-lethal
damage to at least a portion of the tumour cells or tissue.
In a particularly preferred embodiment, the means of immunogenic tumour cell
death therapy comprises irradiation, including ionizing radiation such as gamma
rays, UV-C irradiation, targeted radiation, and the like.
In another embodiment, the therapy comprises irradiation, including ionizing
radiation such as gamma rays, UV-C irradiation, targeted radiation, and the like,
combined with administration of the immunomodulator, n the dose of
radiation is onated. Suitable ation dosage regimes include a single full
dose or about 3 fractions each comprising about 40 % or more of the full dose, or
about 5 fractions each comprising about 30% or more of the full dose, or doses and
fractions as known to those skilled in the art.
In another particularly preferred embodiment, the means of immunogenic cell death
therapy comprises irradiation, including ionizing radiation such as gamma rays, UVC
irradiation, targeted radiation, and the like, combined with administration of the
modulator, resulting in an abscopal .
Ionizing radiation can reduce tumour growth outside the field of radiation, known as
the abscopal effect, from the Latin "ab scopus", "away from the target". gh it
has been reported in multiple malignancies, the abscopal effect remains a rare and
poorly understood event. Their rare occurrence reflects the fact that, by itself,
standard radiotherapy is inadequate at subverting the existing immuno-suppression
characteristic of the microenvironment of an established tumour.
An abscopal effect is defined as a measurable response in any of the measurable
lesions outside the radiation field, as assessed by .
Specifically, radiation therapy causes upregulation or release of signals within a
tumour that invoke Dendritic Cell (DC) migration to the tumour, uptake of tumour
antigens, and tion. These antigen-loaded DC migrate to regional lymph
nodes and activate tumour antigen-specific T cells capable of tumour destruction.
Finally, radiation therapy may eliminate regulatory immune cell populations that
would otherwise hinder the development of effective antitumor T-cell responses
(Morse et al, commentary; Oncology: Aug 2008. Vol. 22 No. 9).
In another red embodiment, the means of immunogenic cell death y
comprises irradiation, including ionizing radiation such as gamma rays, UV-C
irradiation, targeted radiation, and the like, combined with administration of the
immunomodulator, ing in an abscopal effect, as demonstrated by sion
of local s and/or distant ases.
In another ularly preferred embodiment, the invention provides an
immunomodulator for use in the treatment of a neoplastic disease in a patient
intended to undergo immunogenic cell death therapy by cyberknife, simultaneously,
tely or sequentially with administration of the immunomodulator, optionally
for the treatment of colorectal cancer or metastases derived therefrom.
A suitable dosage schedule according to the present invention includes
administration of the modulator at 2 weeks prior to and on the day of said
ablative or immunogenic tumour cell death therapy, followed by further doses of
said immunomodulator 2 weeks and 4 weeks later. Further doses of
immunomodulator may be administered at weekly or ghtly intervals such as at
8 weeks, 10 weeks and 12 weeks. Preferably the immunomodulator is continued to
be administered at week 16 after ablative or immunogenic cell death therapy and
repeated every 4 weeks fter for up to 12 months following the first dose
given.
In some cases the immunogenic cell death therapies may require open surgical
exposure of the tumour but most can be performed with minimal risk
laparoscopically or percutaneously. In addition to cost savings, the percutaneous
route has the potential for performance under conscious sedation, thus further
reducing potential morbidity.
Radiofrequency ablation (RFA) and cryoablation is used primarily for liver tumours,
is an invasive procedure requiring the insertion of a probe and is not without risk. In
addition to direct tumour destruction, there is strong evidence that anti-tumour
immune responses are ted by the procedure. (Napoletano et al Int J Oncol
2:481-490).
RFA, laser and ave ablation all produce tissue death via hermic injury.
RFA produces thermal injury through the use of alternating electric current in the
radio-frequency range (460-500 kHz). Subsequent ionic ion in the surrounding
tissue causes frictional heat, which then spreads outward from the electrode via
conduction. Suitable RF devices commercially marketed in the United States may
be obtained from RITA Medical Systems Inc., Mountain View, CA, and
Radiotherapeutics, in View, CA. These devices consist of a needle with a
e hub that deploys a variable number of curved electrodes into the adjacent
tissue in a radial manner. The configurations of the multiple electrodes are
designed to produce large spherical thermal injuries. A further device nics,
Burlington, MA) consists of a straight, internally cooled needle electrode. The
internal cooling is ed to prevent charring of the adjacent tissues and thus a
larger thermal injury. Other suitable apparatus include the computer-assisted
radiofrequency generator (Elektrotom 106 HF, Berchtold, ngen, Germany)
optionally ng water-cooled treatment probes (Cool-Tip, ValleyLab, Boulder,
CO). RFA needles, such as those with an active tip of 8 mm (SMK-15; Cotop,
Amsterdam, the Netherlands) may be used in combination with an RF lesion
generator system (Model RFG-3B; ics, Burlington, MA). Treatment
preferably results in a tip temperature of 75-80°C or even above 100 °C in certain
tumours or metastases. If the temperature at the tip is below 50°C, another
ablation in the same location is ably performed.
The leakage of tumour antigens following tumour damage by laser-induced
thermotherapy is supported by the observation that following treatment there is an
enhancement of cytotoxic T cell ses. In a study of 11 patients with hepatic
metastases of colorectal cancer treatment significantly increased the tic
activity of CD3+, CD4+ and CD8+ T cells against an allogenic tumour cell line (Vogl
et al, Cancer Immunol Immunother 2009;58:1557-1563). SABR has also been
shown to create an environment leading to enhanced anti-tumour immune
responses by inducing tumour antigen leakage in the presence of DAMPs such as
heat shock proteins (Finkelstein et al. Clin and Dev Immunol; vol 201 1: ID 439752).
We propose that these effects can be induced using low-dose irradiation delivery in
conjunction with an immunotherapeutic agent which will establish a self-sustaining
long-term immunological response to the tumour and promote anti-tumour
immunity.
icant complications are rare with any of the RFA ques, although most
series report a few ts with minor complications requiring no specific
treatment. Among the reported complications, the most common is pain, although
this is typically of short on. Other reported complications include fever,
intraperitoneal and intrahepatic hemorrhage, hemobilia, hemothorax, diaphragmatic
, l effusion, cholecystitis, elevated transaminase levels, and needle tract
seeding.
tactic ablative radiotherapy (SABR) may be used in the present invention as
a form of physical tumour disruption to induce immunogenic tumour cell death.
SABR is a form of radiosurgery for s in the torso. SABR, which is also
sometimes referred to as stereotactic body radiotherapy or SBRT, has shown
promise for the treatment of both inoperable and operable stage 1 non-small cell
lung cancer (NSCLC). The effective radiosurgical dose was in the range of 15-20
Gy. Systems and methods for performing stereotactic radiosurgery are known in
the art and are disclosed, e.g., in U.S. Patent No. 223, issued to Adler on
May 4 , 1993, and U.S. Patent No. 5,458,125, issued October 17, 1995 to
Schweikard, which are incorporated by reference in their entirety herein.
Microwave ablation may be used as an alternative means of ing thermal
coagulation of tissue es the use of microwaves to induce an ultra-high-speed
(2450 MHz) alternating electric field, resulting in the rotation of water molecules. As
with RFA ave ablation involves placement of a needle electrode ly into
the target tumour. Suitable apparatus include the Acculis Microwave Tissue
Ablation (MTA) system (From Microsulis Medical) which operates at 2.45GHz and
is a very powerful apparatus when compared to Radio ncy Ablation (RFA)
devices and low power 915MHz microwave systems. The system comes with the
choice of a range of needle-like applicators to maximise the types of procedure for
which it can be used: open, laparoscopic and percutaneous. Microwave energy
emits from the tip of the applicator and is absorbed by the surrounding tissue. The
depth of absorption depends on microwave ncy and power. This is controlled
through the Sulis VpMTA generator. At z, the energy will penetrate 2cm into
the tissue. This is the active microwave heating zone. Inside the active ave
heating zone the microwaves rotate the water molecules causing them to heat
rapidly. Heat from the active microwave heating zone then conducts outwards
creating a secondary thermal conduction g zone. This completes the
treatment. The coagulation zone is largely spherical, with a slight tion in the
direction of the shaft of the applicator. By selecting power and time the user can
control both the size and rate of development of the coagulation zone. The active
microwave heating creates visible steam formation within the target zone and this
can be monitored in real time by intra-operative ultrasound or CT imaging giving
real time control.
ed complications of microwave ablation are similar to those reported for RFA
and are typically mild, including pain, fever, liver enzyme elevation, ascites/pleural
effusion, diaphragm injury, and needle track seeding.
In an alternative embodiment, laser ablation may be used. This que uses a
neodymium yttrium aluminium garnet (Nd-YAG) laser to deliver high-energy light to
the target lesion. The light subsequently scatters within the tissue, converting to
heat. l fibres are deposited into the tumour through a percutaneously placed
needle. Multiple fibres can be inserted into the tumour at regularly spaced intervals
to enlarge the area of necrosis. Treatment times vary but may exceed 1 hour for a
large ablation. Another alternative is focal laser on (FLA) which is defined as
the thermal ction of tissue by laser. FLA action is based on a photothermal
effect; the thermal action results from the absorption of radiant energy by tissue
receptive chromophores inducing heat energy in a very short time (few s).
This increased temperature may cause irreversible damages and remotely in vivo
ction. The thermal effect depends on the amount of heat energy delivered but
also on the depth of light distribution. Consequently, the deep tissue damage is
dependent on the wavelength of the laser in action. Due to weak absorption by
water or hemoglobin, wavelengths between 590 and 1064 nm are classically used
to obtain a deeper tissue penetration. The extension of thermal tissue damage
depends on both temperature and g duration. Cell viability is in relation with
thermostability of several critical proteins. Irreversible n denaturation may
occur around 60°C, while over 60°C, coagulation is quasi-instantaneous, between
42 and 60°C, the red range for use in this invention, a thermal damage is
obtained with longer heating periods. The area submitted to supraphysiological
hyperthermia less than 60°C will develop coagulative necrosis in 24 to 72 h after
treatment.
Cryoablation may be used as an ative to causing thermal injury to tissue
through heating. Cryoablation destroys tissue by delivering subfreezing
temperatures via probes through which a cryogen is circulated. ar death
results from direct freezing, denaturation of cellular proteins, cell ne
rupture, cell dehydration, and ischemic hypoxia. Although freezing potentially
produces the largest ablations of all the l techniques, the procedure in its
most commonly practiced form requires general anaesthesia and laparotomy for
probe placement. Cryoablation may be performed at a temperature of about minus
40 s Celsius, or about minus 60 degrees Celsius,.or may be carried out
using liquid nitrogen (-170 degrees Celsius) and d by a contact method with
the Cryobar equipment (Tori). During cryoablation the interface of the
frozen/unfrozen liver can be assessed easily with intra-operative ultrasound by the
appearance of an echogenic edge with posterior acoustic shadowing, an advantage
of cryoablation over RFA In certain embodiments therefore, cryoablation is a
preferred method of inducing immunogenic tumour cell death, compared to thermal
methods.
The complication rate for lation may be higher than that for RFA, although
cryoablation may not be as limited by lesion size. In addition, there exists evidence
that lung inflammation may be a complication unique to lation and may be
related to the thawing phase of the ablated tissue.
In an alternative embodiment, ethanol ablation may be used as the ablative
therapy. Percutaneous ethanol injection (PEI) is relatively simple to perform, and is
the least expensive, requiring minimal equipment. PEI is performed by the injection
of absolute alcohol through a needle placed percutaneously directly into a .
The necrosis produced by ethanol injection results from cellular dehydration and
tissue ischemia from ar thrombosis. Ethanol ablation may also be considered
for recurrent or partially d disease previously managed with an alternative
minimally invasive technique. Contraindications to treatment include those
mentioned above for RFA in addition to thrombosis of the main portal vein. ts
with obstructive jaundice may also be at sed risk for complications such as
bile peritonitis. As with the aforementioned ques, the complete ablation rate
with ethanol is higher for small tumours.
Embolization is an established technique for the treatment of hepatic tumours.
Embolization is an endovascular technique, (performed from within the blood
vessels) to block vessels of the tumour. Embolization is performed using catheters
and angiographic techniques. For the embolization procedure, a very tiny catheter
is ed from the groin directly into the tumour vessels around the brain, head
and neck, or spine, for example. Under X-ray guidance, material is injected through
the catheter to ently block and close off the vessels of the tumour. Materials
used include particles or small platinum coils. The selection of c agent is
directed by a e between risk and efficacy. r particles (45-150 microns)
and liquid embolic agents (bucrylate, ethanol, ethylenevinylalcohol) penetrate
tumour better and achieve a higher degree of necrosis. The operator 's selection of
embolic agent is directed by a balance between risk and efficacy. The critical size
of microparticles is generally considered to be above 150 s. In one study,
populations of CD4+ T cells specific for epitopes of the tumour antigen a -
fetoprotein were significantly expanded during and after zation (Ayaru et al. J
lmmunol.2007;178:1914-1922). These T cells produced Th1 cytokines (IFN-g and
TNF-a) but not the Th2 cytokine IL-5 and the authors concluded that these results
provided a rationale for combining embolization and immunotherapy. In r
study (Zerbini et al Cancer Res 6:1 139-1 146), increased numbers of Th2
cells were demonstrated in patients one month after embolization, and the cells had
increased expression of markers of cytotoxic activity. These T cells did not,
however, prevent relapse of the disease and one patient developed a new nodule,
the antigens of which were not recognized by the T cells, ting immune
escape. Thus additional immunotherapeutic strategies to maintain immune
recognition are required.
In a yet further embodiment, photodynamic therapy may be used as the ablative
y. Photodynamic therapy es administering to a subject an effective
amount of a photosensitizer and irradiating said subject with light absorbed by said
photosensitizer. The effective amount of a photosensitizer may be in the range of
0.05 to 10 mg/kg, or 0.05 to 1 mg/kg, or 1 to 10 mg/kg. In the first step of PDT for
cancer treatment, a photosensitizing agent is injected into the bloodstream. The
agent is absorbed by cells all over the body but stays in cancer cells longer than it
does in normal cells. imately 24 to 72 hours after injection , when most of
the agent has left normal cells but remains in cancer cells, the tumour is exposed to
light. The photosensitizer in the tumor absorbs the light and produces an active
form of oxygen that destroys nearby cancer cells. In addition to directly killing
cancer cells, PDT appears to shrink or destroy tumours in two other ways. The
photosensitizer can damage blood vessels in the tumour, y preventing the
cancer from receiving necessary nts. As required in this invention, PDT also
tes the immune system to attack the tumour cells. The light used for PDT can
come from a laser or other sources. Laser light can be directed through fiber optic
cables (thin fibers that transmit light) to deliver light to areas inside the body. For
example, a fiber optic cable can be inserted through an endoscope (a thin, lighted
tube used to look at tissues inside the body) into the lungs or esophagus to treat
cancer in these . Other light sources include light-emitting diodes (LEDs),
which may be used for surface tumours, such as skin cancer.
The photosensitizer may be administered intravenously or intratumourally and the
irradiation is preferably localized to the tumours. Suitable ensitizers include
benzoporphyrin derivative (BPD), e.g. BPD-MA, EA6, or B3 or a green porphyrin.
Such photosensitizers may be formulated in a liposomal formulation.
The patient whom is to undergo immunogenic tumour cell death or ablative tumour
disruption therapy according to the present invention may do so simultaneously,
separately or sequentially with administration of the immunomodulator. Preferably
the modulator is administered to the patient prior to the physical tumour
disruption therapy of the tumour . More specifically, the immunomodulator
may be administered to the patient between about 4 weeks and 1 week prior to the
tumour disruption y. Preferably, the immunomodulator may be administered
as one or more aliquots each containing an effective amount of the
modulator which may be administered at one or more time intervals
between 4 weeks and 1 week prior to the tumour disruption therapy and/or the
immunomodulator may be applied after the therapy. Even more preferably, the
modulator may be administered as one or more aliquots each containing an
effective amount of the modulator which may be administered at one or
more time intervals between 4 weeks and 1 week after the tumour disruption
therapy and/or the immunomodulator may applied after the therapy, and ed
on at least about 2 , 4 , 6 , 8 , 10, 12, 15, 20 or more occasions before or after the
therapy.
In one embodiment of the present invention, the immunomodulator may be in the
form of a medicament administered to the patient in a dosage form and/or in a
schedule as set out in the examples.
In an aspect of the invention, the effective amount of the immunomodulator may be
administered as a single dose. Alternatively, the effective amount of the
immunomodulator may be stered in multiple (repeat) doses, for example two
or more, three or more, four or more, five or more, ten or more, or twenty or more
repeat doses. Preferably, the immunomodulator is administered between about 4
weeks and 1 day prior to tumour disruption therapy of the tumour tissue, more
preferably between about 4 weeks and 1 week, or about n 3 weeks and 1
week, or about between 3 weeks and 2 weeks. Administration may be presented in
single or multiple doses.
A container according to the invention in certain instances, may be a vial, an
e, a syringe, capsule, tablet or a tube. In some cases, the mycobacteria
may be lyophilized and formulated for resuspension prior to administration.
However, in other cases, the mycobacteria are suspended in a volume of a
pharmaceutically acceptable liquid. In some of the most preferred embodiments
there is provided a container comprising a single unit dose of mycobacteria
suspended in pharmaceutically acceptable carrier wherein the unit dose ses
about 1 x 106 to about 1 x 1010 CFU of mycobacteria. In some very specific
embodiments the liquid comprising suspended mycobacteria is provided in a
volume of between about 0.1 ml and 10 ml, about 0.3 ml and 2ml or about 0.5 ml
and 2 ml. It will further be understood that in certain ces a composition
sing mycobacteria in a containment means is frozen (i.e. maintained at less
than about zero degrees Celsius). The foregoing compositions provide ideal units
for immunotherapeutic applications described herein.
Embodiments discussed in the context of a methods and/or ition of the
invention may be employed with respect to any other method or composition
described herein. Thus, an embodiment pertaining to one method or ition
may be applied to other methods and compositions of the invention as well.
In some cases heat-killed mycobacteria is administered to specific sites on or in a
subject. For example, the cterial compositions according to the invention,
such as those comprising M. obuense in ular, may be administered adjacent
to tumours or adjacent to lymph nodes, such as those that drain tissue surrounding
a tumour. Thus, in certain ces sites administration of cterial
ition may be near the posterior cervical, tonsillar, axillary, inguinal, anterior
cervical, sub-mandibular, sub mental or superclavicular lymph nodes. Such sites of
administration may be on the right side, on the left side, or on both sides of the
body. In certain very specific embodiments, mycobacterial compositions are
delivered close to the axillary, cervical and/or inguinal lymph nodes. For example, a
dosage of the cteria may distribute into tissues adjacent to the right and left
axillary lymph node and the right and left inguinal lymph nodes.
In a very specific embodiment a dosage of cteria is administered to a
subject by intradermal injection wherein the dosage is distributed to the axillary and
inguinal on both sides of the body and wherein there are two injections (i.e. two
wheals) at each site.
In some further embodiments of the invention, methods of the invention e the
administration of 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 or more doses of mycobacteria ted
by a period of one day or more. In certain preferred embodiments such separate
doses will be separated by several days, one week, two weeks, one month or
more. For example, methods according to the invention may comprise
stering 1 to 5 doses of cteria over a period of three weeks or more.
In yet further embodiments, methods of the invention comprise administering 1 to 5 ,
1 to 4 , 1 to 3 , 1 to 2 or 2 doses of mycobacteria over a period of about three weeks.
Each dose administered may be the same or different dosage relative to a previous
or subsequent dose administration. For example, in certain cases, it is preferred
that a dosage of mycobacteria is lower than any dosage that was previously
administered. Thus, in some specific cases, a dose of heat-killed mycobacteria will
be administered at about half of the dosage that was administered in any previous
treatment. Such methods may be preferred in certain instances where the t's
immune response to the mycobacteria is greater during subsequent therapies.
Thus in certain cases, the immunomodulator may be administered a minimal
number of times for example, in less than 10, 9 , 8 , 7 , 6 , 5 , 4 , 3 or fewer separate
dosage administrations. In some cases the mycobacterial composition is
administered twice. Alternatively, the immunomodulator may be stered for
the length of time the cancer or tumour(s) is present in a patient or until such time
the cancer has regressed or stabilized. The immunomodulator may also be
continued to be stered to the ts once the cancer or tumour has
regressed or stabilised.
Mycobacterial compositions according to the invention will comprise an effective
amount of cteria typically dissolved or dispersed in a pharmaceutically
acceptable carrier. The phrases "pharmaceutical or pharmacologically acceptable"
refers to molecular entities and compositions that do not produce an adverse,
allergic or other untoward reaction when administered to an , such as, for
example, a human, as appropriate. The preparation of an ceutical
composition that contains mycobacteria will be known to those of skill in the art in
light of the present disclosure, as exemplified by ton's Pharmaceutical
Sciences, 18th Ed. Mack Printing Company, 1990, Moreover, for animal (e.g.,
human) stration, it will be understood that preparations should meet ity,
pyrogenicity, general safety and purity standards. A specific example of a
pharmacologically acceptable carrier as described herein is borate buffer or sterile
saline solution (0.9% NaCI).
As used herein, aceutically acceptable carrier" includes any and all solvents,
dispersion media, coatings, surfactants, antioxidants, preservatives (e.g.,
antibacterial agents, antifungal agents), isotonic agents, absorption delaying
agents, salts, preservatives, drugs, drug stabilizers, gels, binders, ents,
disintegration agents, lubricants, sweetening agents, flavouring , dyes, such
like materials and combinations f, as would be known to one of ordinary skill
in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack
Printing Company, 1990, pp. 1289-1329).
In a preferred embodiment, the immunomodulator is administered via a parenteral
route selected from subcutaneous, intradermal, subdermal, intraperitoneal,
intravenous and intravesicular ion. Intradermal injection enables delivery of an
entire proportion of the mycobacterial ition to a layer of the dermis that is
accessible to immune surveillance and thus capable of electing an anti cancer
immune se and promoting immune cell proliferation at local lymph nodes.
Though in highly preferred ments of the invention mycobacterial
compositions are administered by direct intradermal injection, it is also
contemplated that other methods of administration may be used in some case.
Thus in n ces heat-killed mycobacteria of the present ion can be
administered by injection, infusion, continuous infusion, intravenously,
intradermally, intraarterially, intraperitoneally, intralesionally, intravitreally,
intravaginally, intrarectally, topically, intratumorally, intramuscularly,
intraperitoneally, subcutaneously, subconjunctival, intravesicularlly, mucosally,
intrapericardially, intraumbilically, intraocularally, orally, intracranially,
intraarticularly, intraprostaticaly, intrapleural^, intratracheally, intranasally, topically,
locally, inhalation (e.g. aerosol inhalation), via a catheter, via a , or by other
method or any combination of the forgoing as would be known to one of ordinary
skill in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed.
Mack Printing Company, 1990). More ably, administration by the parenteral
route does not comprise intratumoural injection of mycobacterial cell wall extract.
All publications mentioned in the above specification are herein incorporated by
reference. Various modifications and variations of the described methods and
system of the present invention will be apparent to those d in the art without
departing from the scope and spirit of the present invention. Although the t
invention has been described in connection with specific preferred embodiments, it
should be understood that the invention as claimed should not be unduly limited to
such specific embodiments. Indeed, various modifications of the described modes
for carrying out the invention which are s to those skilled in biochemistry and
logy or d fields are intended to be within the scope of the following
claims.
The invention is further described with reference to the following non-limiting
Examples.
Example 1
To investigate the invention, we conducted a study in female Balb/c mice injected
subcutaneously with an inoculum of Renca tumour cells and treated with irradiation
therapy in combination with IMM-101 (Mycobacterium obuense, rough strain, heat-
killed).
y, adult mice were maintained under SPF conditions at lled temperature
(23±2°C), Humidity (45±10%) and photoperiod (12 hr light/12 hr dark). They were
provided with water and food at libitum. Mice were individually tagged for identity.
At day 0 , mice received subcutaneously an inoculum of 105 Renca tumour cell in a
0.2ml volume of RPMI 1640 medium in their right flank. Tumour ishment and
growth was monitored daily. Once tumours became palpable (100-200mm 3 on day
) mice were randomised and divided into three groups. Group 1 was left
ted. Group 2 and 3 received the following treatments: Group 2) two cycles of
one irradiation of the tumour at 2Gy/day every two days for a total of three
irradiations/cycle (total irradiation dose 12Gy, schedule ]x2 starting on day
and continuing on day 28, 30, 32, 35 and 37); Group 3) two cycles of irradiation
as described above in synergy with IMM-101 (0.1 mg) injected subcutaneously
about every two days, starting on day 25 and repeated on day 28, 30, 32, 35, 37,
39, 42 etc.
Animals were monitored daily and length and width of tumour measured twice a
week with calipers to estimate tumour volume (1/2 x length x width2) . Individual
body weight and tumour volume were recorded for each mouse. Data was d
to follow changes in tumour volume over time in the three treatment groups (Fig. 1) .
We found that ed to control untreated animals, mice receiving irradiation
and 1 showed a significant reduction in tumour volume (Anova, s
comparison). This provides evidence that said combination treatment provides an
improved therapy and ed survival outcome.
Example 2
An investigative study of a preparation of heat-killed whole cell M. obuense (IMM-
101) in combination with radiation-induced immunogenic tumour necrosis in
patients with previously treated colorectal cancer was conducted in patients
according to the protocol described in Table 1. Patients were subjected to a dose
of M. obuense 1 on the same day as establishment of the baseline and
insertion of the al seeds required for t focusing of cyberknife energy;
subsequent SBRT using cyberknife technology to induce tumour necrosis was
administered at day 14, together with a further dose of M. obuense (IMM-101). The
patients received a further dose of M. obuense 01) on day 28 and then
continued to receive M. obuense (IMM-101) doses at ghtly intervals between
week 8 and 12, inclusively, whereupon the dose frequency was reduced to monthly
throughout the remaining period of the year-long study. Patients were then
assessed for tumour regression and disease isation at week 12 and every
twelve weeks thereafter. The results show tumour regression after week 12 and
then a prevalence of disease stabilisation at week 24 following continued
administration of M. obuense (IMM-101) after the initial application of the
cyberknife.
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References
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Claims (13)
1. Use of an immunomodulator comprising a non-pathogenic heat-killed whole cell Mycobacterium in the preparation of a medicament for use in the treatment and/or control of a neoplastic disease in a patient intended to undergo immunogenic cell death therapy 5 simultaneously, separately or sequentially with administration of the immunomodulator, wherein the Mycobacterium is selected from M. obuense; wherein said immunogenic cell death therapy is selected from microwave irradiation, targeted radiotherapy, embolisation, cryotherapy, ultrasound, high intensity d ultrasound, nife, hyperthermia, radiofrequency on, cryoablation, electrotome heating, hot water injection, l 10 injection, embolization, radiation re, photodynamic y, laser beam irradiation, and combinations thereof; wherein said immunogenic cell death therapy is to be carried out at a sub-optimal level that is not intended to fully remove or eradicate the tumour of said neoplastic disease.
2. The use according to claim 1, wherein the tumour is metastatic. 15
3. The use according to claim 1 or 2, wherein the non-pathogenic heat-killed Mycobacterium is the rough variant.
4. The use according to any one of claims 1 to 3, n the non-pathogenic lled Mycobacterium is for administration via the parenteral, oral, sublingual, nasal or pulmonary route. 20
5. The use according to claim 4, wherein the parenteral route is selected from subcutaneous, intradermal, subdermal, intraperitonal, intravenous, or intravesicular injection.
6. The use according to claim 5, wherein the parenteral route does not comprise intratumoural injection.
7. The use according to any one of claims 1 to 6, n said immunogenic cell death 25 therapy is by ionizing radiation.
8. The use according to any one of claims 1 to 7, wherein administration of said medicament is prior to and/or after the immunogenic cell death therapy.
9. The use according to claim 8, n administration of said ment is between 4 weeks and 1 week prior to and/or after the immunogenic cell death therapy.
10. The use according to claim 9, wherein said administration of the ment comprises administration of one or more aliquots of an effective amount administered at one or more time intervals between about 4 weeks and 1 week prior to and/or after the immunogenic cell death therapy and continued to be d to the patient after ent for 5 regression of the tumour.
11. The use according to any one of claims 1 to 10, wherein said medicament is administered to said patient after immunogenic cell death of the tumour cells, and/or during stabilisation of the disease.
12 The use according to any one of claims 1 to 11, wherein said tumour is associated 10 with a cancer selected from prostate cancer, liver cancer, renal cancer, lung cancer, breast cancer, colorectal cancer, breast cancer pancreatic cancer, brain cancer, cellular cancer, lymphoma, leukaemia, gastric cancer, cervical cancer, ovarian cancer, thyroid cancer, melanoma, oma, head and neck cancer, skin cancer and soft tissue sarcoma.
13. The use according to claim 12, wherein said tumour is associated with colorectal 15 cancer. 14 The use according to any one of claims 1 to 13, wherein said therapy ses an abscopal effect on a neoplastic e in a patient.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB1120779.2 | 2011-12-02 | ||
GBGB1120779.2A GB201120779D0 (en) | 2011-12-02 | 2011-12-02 | Cancer therapy |
PCT/GB2012/052992 WO2013079980A1 (en) | 2011-12-02 | 2012-12-03 | Immunogenic treatment of cancer |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ624994A NZ624994A (en) | 2016-10-28 |
NZ624994B2 true NZ624994B2 (en) | 2017-01-31 |
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