21-12-2012, 03:13 PM
Autoimmunity associated with immunotherapy of cancer
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Introduction
Immunotherapy holds much promise for the treatment of cancer.
The immune system is capable of dramatic and decisive responses
against infectious disease, which is accomplished with exquisite
specificity against antigen. Components of immunity are seen as
potentially more specific weapons to direct against tumors than
chemotherapy or radiation. With our expanding knowledge of tumorassociated
antigens (TAAs), there are many different approaches
being developed to direct immunity against transformed cells.
Immunotherapies may involve the active generation of immunity
to TAA, via vaccination with peptides or peptide-pulsed
dendritic cells.1 In addition, administration of immune modulators,
such as cytokines, can boost existing antitumor immunity and
target immune effector cells to sites of tumor growth.2 Monoclonal
antibodies harness both innate and adaptive immune mechanisms
and direct them against tumor cells.3 In addition, the effector
functions of cytotoxic T lymphocytes have proven them to be
particularly useful in targeting TAAin adoptive immunotherapeutic
protocols.4
Autoimmunity associated with adoptive immunotherapy
Adoptive immunotherapy is a very promising approach to treating
cancer that involves the isolation of leukocytes and their activation
and expansion in vitro followed by infusion into patients. Advantages
of this type of approach include the opportunity to manipulate
and activate lymphocytes away from the in vivo immunosuppressive
environment, and their expansion to vast numbers, thereby
circumventing many regulatory checkpoints and delivering “instant”
immunity. Adoptive immunotherapy has been demonstrated
to induce regression of established tumors, often complete, in both
mouse models of disease and in patients.4 However, apart from
Epstein-Barr virus–associated malignancies, this form of therapy
targets antigens expressed on some normal tissues besides tumor
cells, and immune-mediated toxicity has been observed in the
treatment of both mice and humans
Tumor-infiltrating lymphocytes and melanoma
Tumor inhibition has been described using adoptive immunotherapy
in various animal models over the past 50 years, but
antigen specificity and its expression on normal tissue were largely
undefined in earlier models.6,7 More recently, mouse tumor models
with known tumor antigens also expressed on self-tissues have
become available and effective antitumor responses after adoptive
immunotherapy has been observed.8 However, immune-mediated
toxicity has been observed in these mouse models targeting normal
tissues, including skin, eye, colon, and the B-cell compartment as
summarized in Table 1. In the following discussion, we focus on
these toxicities following adoptive immunotherapy in humans.
One of the most promising applications of adoptive immunotherapy
in the clinic involves the use of tumor-infiltrating lymphocytes
to treat melanoma. Lymphocytes derived from tumors can be
expanded to yield many billions of cells that are reactive with a
range of melanoma antigens, including gp100, MART-1, and
tyrosinase.
Genetically redirected T cells in adoptive immunotherapy
By far the greatest application of adoptive immunotherapy has
been in the melanoma setting as described in “Tumor-infiltrating
lymphocytes and melanoma.” This is largely because of the
availability of specific T cells, and extension to other common
cancers is restricted by a lack of availability of endogenous T cells
of appropriate specificity. However, T cells reactive with a range of
common cancers can be generated by genetic modification of
peripheral blood lymphocytes with chimeric antigen receptors
(CARs), whose specificity is derived from monoclonal antibodies
specific for cell surface TAA. CAR-modified T cells have been
used in clinical trials for a range of cancers, including ovarian
cancer, neuroblastoma, colon cancer, and lymphoma.13 The use of
CAR-modified T cells is in its infancy, and only limited antitumor
effects have been described to date. Nevertheless, in a phase
1 study for renal cell carcinoma (RCC) targeting the TAA carbonic
anhydrase IX, adoptive transfer of gene-modified T cells led to
grade 3 to 4 liver toxicity in 3 of 7 patients treated. Toxicity was
thought to be the result of T cells targeting the CAIX antigen also
present on bile ducts.14 Toxicity was resolved in this study after
cessation of adoptive T-cell transfer or administration of steroids.
CAR-modified T-cell activity against normal cells was also
observed in a clinical study targeting CD19 for the treatment of
follicular lymphoma.15 The CAR was composed of a single-chain
anti-CD19 antibody linked to CD28 and the -chain of the
CD3-TCR complex. In this study, dramatic regression of malignant
cells was observed, but a prolonged depletion of normal B cells
was also observed, leading to greatly decreased levels of serum
immunoglobulin. Although low levels of serum antibody are
concerning, administration of exogenous immunoglobulin can
correct for this deficiency, thereby providing protection against
infection. In another study targeting CD19 with CAR-modified
T cells, this time for chronic lymphocytic leukemia, treatment was
well tolerated in 3 patients receiving T-cell transfer in the absence
of prior lymphodepletion, with only transient fevers experienced.
However, a patient receiving T cells after lymphodepletion developed
hypotension, dyspnea, and renal failure and died 4 days after
treatment.16 Death in this case was not thought to be the result of
treatment and was attributed to sepsis because of infection.