Cancer immunotherapy ASI - active specific immunotherapy

Cancer immunotherapy attempts to stimulate the immune
system to reject and destroy tumors. Immuno cell therapy
for cancer was first introduced by Rosenberg and his
colleagues of National Institute of Health USA. In the
late 80s, they published an article in which they reported
a low tumor regression rate (2.6-3.3%) in 1205 patients
with metastatic cancer who underwent different types of
active specific immunotherapy (ASI), and suggested that
Immuno Cell Therapy with specific chemotherapy is the
future of cancer Immunotherapy. In the beginning
Immunotherapy treatments involved administration of
cytokines such as Interleukin with an aim of inducing
the lymphocytes which will carry their activity of
destroying the tumor cells. Thereafter the adverse effects
of such intravenously administered cytokines lead to
the extraction of the lymphocytes from the blood and
culture-expand them in the lab and then to inject the
cells alone enable them destroy the cancer cells .

Though the concept of this treatment started in the US in
80s, fully fledged clinical treatments on a routine basis
have been in practice in Japan since 1990. Randomized
controlled studies in different cancers with significant
increase in survival and disease free period have been
reported and its efficacy is enhanced by
20 -- 30% when cell based immunotherapy is combined with
other conventional treatment methods.

BCG immunotherapy for early stage (non-invasive)
bladder cancer utilizes instillation of attenuated live
bacteria into the bladder, and is effective in preventing
recurrence in up to two thirds of cases. Topical
immunotherapy utilizes an immune enhancement cream
(imiquimod) which is an interferon producer causing the
patients own killer T cells to destroy warts,, actinic
keratoses, basal cell cancer, vaginal intraepithelial
neoplasia., squamous cell cancer, cutaneous
lymphoma, and superficial malignant melanoma.
Injection immunotherapy uses mumps, candida the HPV
vaccine, or trichophytin antigen injections to
treat warts (HPV induced tumors). Lung cancer has been
demonstrated to potentially respond to immunotherapy.

In many parts of Asia, Medicinal mushrooms are thought to
be able to boost the immune system naturally. Cellular and
animal research has shown that Agaricus blazei may
stimulate immune system cells and the production of
interferons and interleukins (reviewed by G. Hetland).
Mushroom isolates like PSK also are used to increase
immune system parameters (reviewed by Kobayashi). Used
in conjunction with chemotherapy, PSK has increased the
survival time of cancer patients in randomized, control
studies, with a variety of cancer types.



Autologous Immune Enhancement Therapy (AIET)

In the multipronged approach to treat CANCER, one very
useful latest weapon would be AIET which is in clinical
practice in Japan since 90s for more than 15 years with
good effectiveness and several clinical trials and
researches are reported from institutions all over the
world including from the US. AIET is a treatment method in
which some immune cells are taken out of a patient's body
which are cultured and processed to be activated or to
acquire additional functions until their resistance to
cancer is strengthened, then the cells are put back in the
body. Researchers have found that the thus activated
immune system might also be able to determine the
difference between healthy cells and cancer cells to
eliminate the cancer cells from the body. In AIET,
specific type of cells mainly the NK cells and T
lymphocytes are isolated from the peripheral blood of the
cancer patients (during remission in patients who undergo
chemotherapy) by proven methods, expanded to 25 – 30 fold
and activated and then reinfused back into the patient’s
body. These cells act against the cancer cells effectively
and recharge the immune system. Upon encountering a tumor
cell, the activated NK cell attaches to the membrane of
the cancer cell and injects toxic granules which dissolve
the target cell. In less than five minutes, the cancer
cell dies and the NK cell moves on to its next target
cancer cell. A single NK cell can destroy up to 27 cancer
cells before its lifespan. This is the mechanism by which
AIET is effective in Cancer therapy.


This utilizes dendritic cells to activate a cytotoxic
response towards an antigen. Dendritic cells, a type of
antigen presenting cell, are harvested from a patient.
These cells are then either pulsed with an antigen or
transfected with a viral vector. The activated dendritic
cells are then placed back into the patient; these cells
then present the antigens to effector lymphocytes (CD4+ T
cells, CD8+ T cells, and in specialized dendritic cells, B
cells also). This initiates a cytotoxic response to occur
against these antigens and anything that may present these
antigens. One use for this therapy is in cancer
immunotherapy. Tumor Antigens are presented to dendritic
cells, which cause the immune system to target these
antigens, which are often expressed on cancerous
cells. The Dendreon product candidate Provenge is one
example of this approach.


Adoptive cell therapy (ACT) using autologous
tumor-infiltrating lymphocytes is an effective treatment
for patients with metastatic melanoma; this is based
on adoptive immunity.

Adoptive cell transfer, or "ACT," uses T cell-based
cytotoxic responses to attack cancer. T cells that have a
natural or genetically engineered reactivity to a
patient's cancer are expanded, made more effective, in
vitro using a variety of means and then adoptively
transferred into a cancer patient.

For example, T cells with a naturally occurring reactivity
to a patient’s cancer can be found infiltrated in the
patient's own tumors. The tumor can be harvested, and
these tumor-infiltrating lymphocytes (TIL) can then be
expanded, or made more effective, in vitro using high
concentrations of interluekin-2 (IL-2), anti-CD3 and
allo-reactive feeders. These T cells can then be
transferred back into the patient along with exogenous
administration of IL-2 to further boost their activity.

Thus far, a 51% objective response rate has been observed;
and in some patients, tumors shrank to undetectable
size.

The initial studies of adoptive cell transfer using TIL,
however, revealed that persistence of the transferred
cells in vivo was too short. Before reinfusion,
lymphodepletion of the recipient is required to eliminate
regulatory T cells as well as normal endogenous
lymphocytes that compete with the transferred cells for
homeostatic cytokines. Prior
lymphodepletion to transfer of the expanded TIL was made
by total body irradiation. The trend for increasing
survival as a function of increasing lymphodepletion was
highly significant (P=0.007). Transferred cells
expanded in vivo and persisted in the peripheral blood in
many patients, sometimes achieving levels of 75% of all
CD8+ T cells at 6-12 months after infusion.

Morgan et al. (2006) demonstrated that the adoptive
cell transfer of lymphocytes transduced with retrovirus
encoding T cell receptors (TCRs) that recognize a cancer
antigen can mediate anti-tumor responses in patients with
metastatic melanomas.

In such T cell genetic engineering, TCRs that have been
identified to have reactivity against tumor-associated
antigens are cloned into a replication-incompetent virus
that is capable of genomic integration. A patient's own
lymphocytes are exposed to these viruses and then expanded
non-specifically or stimulated using the engineered TCR.
The cells are then transferred back into the patient. This
therapy has been demonstrated to result in objective
clinical responses in patients with refractory stage IV
cancer. The Surgery Branch of the National Cancer
Institute (Bethesda, Maryland) is actively investigating
this form of cancer treatment for patients suffering
aggressive melanomas.

Combination of ACT with such genetic engineering of T
cells has opened possibilities for the extension of ACT
immunotherapy to patients with a wide variety of cancer
types and is a promising new approach to cancer
treatment.

In June 2008, it was announced that US doctors from the
Clinical Research Division led by Dr. Cassian Yee at Fred
Hutchinson Cancer Research Center in Seattle had
successfully treated a patient with advanced skin cancer
by injecting the patient with immune cells cloned from his
own immune system. The patient was free from tumours
within eight weeks of treatment. Dr. Cassian Yee described
the research findings at The Cancer Research Institute
International 2008 Symposia Series. . Responses,
however, were not seen in other patients in this clinical
trial.

Larger trials are now under way.