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Orchestrating an immune response against cancer with engineered immune cells expressing αβTCRs, CARs, and innate immune receptors: an immunological and regulatory challenge.

de Witte MA, Kierkels GJ, Straetemans T, Britten CM, Kuball J - Cancer Immunol. Immunother. (2015)

Bottom Line: Alternatively, transfer of immune cells engineered to express defined T cell receptors (TCRs) and chimeric antigen receptors (CARs) has shown its potential.Here, we focus on innate immune interventions and their orchestration with TCR- and CAR-engineered immune cells.In addition, we discuss how the exploitation of the full potential of cellular immune interventions is influenced by regulatory frameworks.

View Article: PubMed Central - PubMed

Affiliation: Department of Hematology, University Medical Center Utrecht, Room Number Q05.4.301, PO Box 85500, 3508, GA, Utrecht, The Netherlands.

ABSTRACT
Over half a century ago, the first allogeneic stem cell transplantation (allo-SCT) initiated cellular immunotherapy. For several decades, little progress was made, and toxicity of allo-SCT remained a major challenge. However, recent breakthroughs have opened new avenues to further develop this modality and to provide less toxic and equally efficient interventions for patients suffering from hematological or solid malignancies. Current novel cellular immune interventions include ex vivo expansion and adoptive transfer of tumor-infiltrating immune cells or administration of drugs which antagonize tolerizing mechanisms. Alternatively, transfer of immune cells engineered to express defined T cell receptors (TCRs) and chimeric antigen receptors (CARs) has shown its potential. A valuable addition to 'engineered' adaptive immunity has emerged recently through the improved understanding of how innate immune cells can attack cancer cells without substantial side effects. This has enabled the development of transplantation platforms with limited side effects allowing early immune interventions as well as the design of engineered immune cells expressing innate immune receptors. Here, we focus on innate immune interventions and their orchestration with TCR- and CAR-engineered immune cells. In addition, we discuss how the exploitation of the full potential of cellular immune interventions is influenced by regulatory frameworks. Finally, we highlight and discuss substantial differences in the current landscape of clinical trials in Europe as compared to the USA. The aim is to stimulate international efforts to support regulatory authorities and funding agencies, especially in Europe, to create an environment that will endorse the development of engineered immune cells for the benefit of patients.

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a Utilization of T cell receptors, T cell receptors, CARs, and NK cell receptors to transfer desired immune specificities to donor T cells. TAA tumor associated antigen. b Toolbox of immune receptors, vectors for gene transfer, and carrier cells that can be combined with each other to treat different malignancies
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Fig2: a Utilization of T cell receptors, T cell receptors, CARs, and NK cell receptors to transfer desired immune specificities to donor T cells. TAA tumor associated antigen. b Toolbox of immune receptors, vectors for gene transfer, and carrier cells that can be combined with each other to treat different malignancies

Mentions: In order to further increase efficacy of a DLI while reducing toxicity, limitation of the diversity of transferred cells is needed. Most likely, relatively low doses will be sufficient, given they have the correct specificity and are available within a defined immunological subtype which can expand, contract, and provide long-term memory. In addition, some variety must be preserved to allow a diverse repertoire to tackle cancer cells at different targets and to prevent tumor escape mechanisms, such as antigen loss. This goal can potentially be accomplished by taking advantage of T cells genetically engineered to express a single or a variety of diverse tumor-specific immune receptors (Fig. 2a). Already over a decade ago, it has been demonstrated in animal models that the specificity of a T cell can be transferred between T cells by introduction of and TCR genes [22]. These and other observations have been translated to the first series of clinical trials with TCR-transduced T cells with different target antigens for solid malignancies [23]. Tumor-reactive TCRs were classically either isolated from TILs, from peripheral blood of patients responding to immune therapy (MAGE vaccination studies for instance), or from mouse origin. As a consequence, isolated anti-tumor TCRs are restricted toward a limited pool of HLA molecules. To further extend this method to have broader application, it may be technically feasible to generate cellular products harboring multiple tumor-specific immune receptors extracted from a given patient. With innovative techniques, in which the cancer exome is analyzed in a high throughput fashion [24], it is now possible to identify tumor-specific T cells directed against unique tumor antigens in individual patients [25] and as such fully exploit the cancer ‘antigenome’ and overcome HLA barriers. In addition to neo-antigen TCR transfer, novel treatment concepts may arise from identifying highly abundant TCR pairs from TILs, as they seem to be enriched for tumor mutation-specific antigens (unpublished data presented by S. A. Rosenberg at AACR 2014 in San Diego). Although transfer of neo-antigen-specific TCRs and TCR gene capture may bear a huge potential, such a personalized treatment concept will face major medical, regulatory, logistical, and financial challenges, as it creates the need to individualize genetic engineering to multiple (known and unknown) targets varying for every given patient.Fig. 2


Orchestrating an immune response against cancer with engineered immune cells expressing αβTCRs, CARs, and innate immune receptors: an immunological and regulatory challenge.

de Witte MA, Kierkels GJ, Straetemans T, Britten CM, Kuball J - Cancer Immunol. Immunother. (2015)

a Utilization of T cell receptors, T cell receptors, CARs, and NK cell receptors to transfer desired immune specificities to donor T cells. TAA tumor associated antigen. b Toolbox of immune receptors, vectors for gene transfer, and carrier cells that can be combined with each other to treat different malignancies
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4481298&req=5

Fig2: a Utilization of T cell receptors, T cell receptors, CARs, and NK cell receptors to transfer desired immune specificities to donor T cells. TAA tumor associated antigen. b Toolbox of immune receptors, vectors for gene transfer, and carrier cells that can be combined with each other to treat different malignancies
Mentions: In order to further increase efficacy of a DLI while reducing toxicity, limitation of the diversity of transferred cells is needed. Most likely, relatively low doses will be sufficient, given they have the correct specificity and are available within a defined immunological subtype which can expand, contract, and provide long-term memory. In addition, some variety must be preserved to allow a diverse repertoire to tackle cancer cells at different targets and to prevent tumor escape mechanisms, such as antigen loss. This goal can potentially be accomplished by taking advantage of T cells genetically engineered to express a single or a variety of diverse tumor-specific immune receptors (Fig. 2a). Already over a decade ago, it has been demonstrated in animal models that the specificity of a T cell can be transferred between T cells by introduction of and TCR genes [22]. These and other observations have been translated to the first series of clinical trials with TCR-transduced T cells with different target antigens for solid malignancies [23]. Tumor-reactive TCRs were classically either isolated from TILs, from peripheral blood of patients responding to immune therapy (MAGE vaccination studies for instance), or from mouse origin. As a consequence, isolated anti-tumor TCRs are restricted toward a limited pool of HLA molecules. To further extend this method to have broader application, it may be technically feasible to generate cellular products harboring multiple tumor-specific immune receptors extracted from a given patient. With innovative techniques, in which the cancer exome is analyzed in a high throughput fashion [24], it is now possible to identify tumor-specific T cells directed against unique tumor antigens in individual patients [25] and as such fully exploit the cancer ‘antigenome’ and overcome HLA barriers. In addition to neo-antigen TCR transfer, novel treatment concepts may arise from identifying highly abundant TCR pairs from TILs, as they seem to be enriched for tumor mutation-specific antigens (unpublished data presented by S. A. Rosenberg at AACR 2014 in San Diego). Although transfer of neo-antigen-specific TCRs and TCR gene capture may bear a huge potential, such a personalized treatment concept will face major medical, regulatory, logistical, and financial challenges, as it creates the need to individualize genetic engineering to multiple (known and unknown) targets varying for every given patient.Fig. 2

Bottom Line: Alternatively, transfer of immune cells engineered to express defined T cell receptors (TCRs) and chimeric antigen receptors (CARs) has shown its potential.Here, we focus on innate immune interventions and their orchestration with TCR- and CAR-engineered immune cells.In addition, we discuss how the exploitation of the full potential of cellular immune interventions is influenced by regulatory frameworks.

View Article: PubMed Central - PubMed

Affiliation: Department of Hematology, University Medical Center Utrecht, Room Number Q05.4.301, PO Box 85500, 3508, GA, Utrecht, The Netherlands.

ABSTRACT
Over half a century ago, the first allogeneic stem cell transplantation (allo-SCT) initiated cellular immunotherapy. For several decades, little progress was made, and toxicity of allo-SCT remained a major challenge. However, recent breakthroughs have opened new avenues to further develop this modality and to provide less toxic and equally efficient interventions for patients suffering from hematological or solid malignancies. Current novel cellular immune interventions include ex vivo expansion and adoptive transfer of tumor-infiltrating immune cells or administration of drugs which antagonize tolerizing mechanisms. Alternatively, transfer of immune cells engineered to express defined T cell receptors (TCRs) and chimeric antigen receptors (CARs) has shown its potential. A valuable addition to 'engineered' adaptive immunity has emerged recently through the improved understanding of how innate immune cells can attack cancer cells without substantial side effects. This has enabled the development of transplantation platforms with limited side effects allowing early immune interventions as well as the design of engineered immune cells expressing innate immune receptors. Here, we focus on innate immune interventions and their orchestration with TCR- and CAR-engineered immune cells. In addition, we discuss how the exploitation of the full potential of cellular immune interventions is influenced by regulatory frameworks. Finally, we highlight and discuss substantial differences in the current landscape of clinical trials in Europe as compared to the USA. The aim is to stimulate international efforts to support regulatory authorities and funding agencies, especially in Europe, to create an environment that will endorse the development of engineered immune cells for the benefit of patients.

Show MeSH
Related in: MedlinePlus