Cancer Immunotherapy: A Treatment for the Masses

Blattman, Joseph N.; Greenberg, Philip D.

doi:10.1126/science.1100369

Cited by 548 publications

(387 citation statements)

References 42 publications

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“…Adoptive transfer of antigen-specific CD8 T cells into hosts represents a promising approach to treat tumors and viral infections [1][2][3][4]. To generate sufficient numbers of T cells for this therapy, T cells have to be stimulated and expanded in vitro.…”

Section: Introductionmentioning

confidence: 99%

Efficacy of IL‐2‐ versus IL‐15‐stimulated CD8 T cells in adoptive immunotherapy

2008

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We determined the efficacy of in vitro expanded P14 TCR transgenic CD8 T cells to mediate tumor cell elimination and to protect against viral infection in mice. Contrary to previous studies, an adoptive transfer model without lymphodepletion, vaccination or cytokine treatment was used. Antigen-activated P14 T cells cultured in IL-2-containing medium for 7 days (P14 IL-2 ) exhibited potent effector cell functions in vitro but did not confer protection against melanoma growth or viral infection. In contrast, P14 T cells cultured in IL-15 (P14 ) were highly effective in vivo although they displayed only moderate effector functions in vitro. Therapeutic efficacy correlated with the survival of the transferred T cells in the recipients: P14 IL-2 cells disappeared rapidly whereas P14 IL-15 cells persisted for prolonged time. Decreasing the IL-2 concentration in the culture media improved in vivo survival and efficacy but also lowered the cell yield of the cultures. Finally, we could extend the findings with monoclonal P14 T cells to polyclonal CD8 T cells. Thus, in vitro expansion of antigen-specific CD8 T cells in IL-15 allowed the generation of substantial numbers of T cells without inducing terminally differentiated effector cells that turned out to be unfavorable in the transfer model examined here.Key words: Cytotoxic T cells . Rodent . Tumor immunity . Viral IntroductionAdoptive transfer of antigen-specific CD8 T cells into hosts represents a promising approach to treat tumors and viral infections [1][2][3][4]. To generate sufficient numbers of T cells for this therapy, T cells have to be stimulated and expanded in vitro. In most protocols used today, IL-2 is added to the culture medium to ensure T-cell proliferation, differentiation and survival. Besides IL-2, IL-15 also supports CD8 T-cell growth [5]; however, the phenotype and the functional activity of IL-2-versus IL-15-cultured CD8 T cells differ considerably. Manjunath et al. [6] were the first to show that CD8 T cells from P14 TCR-tg mice specific for gp33 epitope of lymphocytic choriomeningitis virus (LCMV) acquired an effector memory phenotype with high cytolytic activity when cultured in the presence of IL-2 whereas addition of IL-15 led to a central memory phenotype with low effector cell functions. Further analysis in the same TCR transgenic system revealed that these two cytokines were equivalent mitogens for antigen-stimulated CD8 T cells but that IL-2 was more potent in inducing amino acid uptake and protein synthesis [7].For adoptive T-cell therapy, it is important to generate CD8 T cells in vitro, which are efficient in inducing tumor regression or virus clearance in vivo. The degree of specific target cell lysis and the amount of antigen-triggered IFN-g production are frequently used to predict the efficacy of CD8 T cells in vivo. However, several recent studies in the pmel-1 TCR-tg model specific for the self/tumor antigen gp100 of B16 melanoma cells indicated that antigen-stimulated CD8 T cells with a less differentiated phenotype were sup...

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Section: Introductionmentioning

confidence: 99%

Efficacy of IL‐2‐ versus IL‐15‐stimulated CD8 T cells in adoptive immunotherapy

2008

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“…2 Following a considerable debate as to whether the immune system can recognize and eliminate tumour cells, recent evidence suggests that immune cells can protect against the development of tumours. 3,4 Nevertheless, the majority of the progress in tumour immunology has been made in the more immunogenic tumours such as melanoma, lymphoma and renal cell carcinoma, whereas a limited success has been achieved with all other less immunogenic cancers. Cancer immunotherapy approach concentrates on killing the tumour cells through various effector cells of the immune system, which include antibody-producing B cells, CD8 þ CTL, CD4 þ helper T cells, NK cells and NKT cells.…”

Section: Overviewmentioning

confidence: 99%

“…First, there are occasional spontaneous regressions of cancers in immunocompetent hosts and higher cancer incidence in immunocompromized patients. 3,25 Second, animals with defined immunological defects are more susceptible to spontaneous and induced tumours compared to normal animals, with many of these tumours rejected when transplanted into normal hosts. 26 Specifically, mice lacking interferon gamma (IFN-g) or IFN-g receptor developed tumours more rapidly and with higher frequency upon their exposure to chemical carcinogen compared to wild-type mice.…”

Section: Immunological Surveillance Theorymentioning

confidence: 99%

“…Amplification of such immune responses against cancers showed therapeutic benefits in experimental models and cancer patients. 3 Although immunosurveillance of transformed cells by the immune system remains one of the most controversial and poorly understood areas in immunology, there is clearly compelling evidence from animal models and human patients that various cells of the immune system can recognize and regulate tumours.…”

Section: Immunological Surveillance Theorymentioning

confidence: 99%

“…43 (2) Class I HLA-restricted, tissue-specific differentiation antigens -these antigens are shared between tumours and the normal tissue from which the tumour arose, and thus they can only be expressed in normal and malignant cells of the same lineage such as melanocytes and tissue of the prostate gland. 44 (3) Class I HLA-restricted widely expressed antigens -genes encode widely expressed tumour antigens that are detected in many normal and tumour tissues with no favoured expression on a certain cancer; for example, carcinoembryonic antigen, which is expressed on colon, breast, lung and gastric carcinomas and on normal gastrointestinal and embryonic tissue. 45 (4) Class I HLArestricted, tumour-specific antigens -they are unique tumour antigens that arise from mutations of normal genes such as cyclin-dependent kinase 4 and b-catenin.…”

Section: Human Tumour Antigens Recognized By T Cellsmentioning

confidence: 99%

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Immunology and immunotherapy approaches for prostate cancer

Elkord

2007

Prostate Cancer Prostatic Dis

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Several mechanisms that impair the immune response to promote tumour progression are reported. These mechanisms aim to reduce the ability of antigen-presenting cells to present antigen and activate naïve T cells to support an active immune response or to create a suppressive environment that induce non-functional tumour-associated antigen-specific T cells. Prostate cancer (PC) alone accounts for 33% of incident cancer cases and about 9% of all cancer-related deaths among men in the USA during 2006. Whereas androgen deprivation has remained the first line of therapy for advanced PC, other therapies are still required due to progression to an androgen-resistant state and eventually loss of control in patients receiving hormonal therapy. Immunotherapy seems to be a promising approach to enhance tumour-specific T-cell responses in different cancers including prostate. More importantly, clinical trials in advanced PC patients have shown that immunotherapy may generate significant clinical responses. Immunology and immunotherapy aspects of PC with focus on prostate-specific antigen will be presented.

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