OncoImmunology
ISSN: (Print) 2162-402X (Online) Journal homepage: http://www.tandfonline.com/loi/koni20
Time to Akt Anniek B van der Waart, Willemijn Hobo & Harry Dolstra To cite this article: Anniek B van der Waart, Willemijn Hobo & Harry Dolstra (2015) Time to Akt, OncoImmunology, 4:5, e1003016, DOI: 10.1080/2162402X.2014.1003016 To link to this article: http://dx.doi.org/10.1080/2162402X.2014.1003016
Accepted online: 03 Feb 2015.
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Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=koni20 Download by: [Universite Laval]
Date: 17 September 2015, At: 20:04
AUTHOR'S VIEW OncoImmunology 4:5, e1003016; May 2015; © 2015 Taylor & Francis Group, LLC
Time to Akt Superior tumor-reactive T cells for adoptive immunotherapy Anniek B van der Waart, Willemijn Hobo, and Harry Dolstra* Department of Laboratory Medicine - Laboratory of Hematology; Radboud university medical center; Nijmegen, The Netherlands
Keywords: adoptive T cell therapy, Akt, dendritic cell, IL-7, IL-15, stem cell transplantation, T-cell differentiation, Wnt
Downloaded by [Universite Laval] at 20:04 17 September 2015
Abbreviations: ACT: adoptive cell therapy; Allo-SCT: allogeneic stem cell transplantation; APC: antigen-presenting cells; CAR: chimeric antigen receptor; DCs: dendritic cells; MiHAs: minor histocompatibility antigens; Tcm: central memory T; TCR: T-cell receptor; Teff: effector T; Tem: effector memory T; TILs: tumor-infiltrating lymphocytes; Tn: naive T; Tscm: stem cell memory T
T cells are crucial players in the protection against cancer, and can be used in adoptive cell therapy to prevent or treat relapse. However, their state of differentiation determines their effectiveness, with early memory cells being the most favorable. Here, we discuss restraining of differentiation to engineer the ultimate tumor-reactive T cell.
T Cells with Stem Cell Flavor T cells are the soldiers of our immune system and crucial forces in the battle against solid and hematological malignancies. Adoptive cell therapy (ACT) exploiting tumor-reactive CD8C T cells is an appealing strategy to treat advanced cancer. A crucial aspect for the functionality of these CD8C T cells in antitumor immunity is their differentiation state.1,2 Upon activation of naive T (Tn) precursor cells, proliferation and differentiation is initiated into the early memory subsets, stem cell memory T (Tscm) cells, and central memory T (Tcm) cells, and their laterarising subsets—effector memory T (Tem) cells and effector T (Teff) cells.1,3 Terminally differentiated Teff cells show potent antitumor killing activity; however, most of them die after a single act of duty. In contrast, the early memory Tscm and Tcm cells not only possess stronger proliferative capacity, they are also capable of differentiating into effector T-cell subsets. Most importantly, they possess a high selfrenewal capacity, which is less profound in the more differentiated T-cell subsets. The supremacy of these early memory T
cells was demonstrated by Klebanoff et al., who described the evolvement of adoptive T-cell therapy in time.2 Using the same pmel-1 melanoma mouse model, comparable antitumor effectiveness was achieved with 500 times less Tscm cells than the “old fashioned” interleukin (IL)-2expanded Teff cells. This demonstrates the superiority of Tscm cells to fight off malignant cells, and makes early memory CD8C T cells the most favorable subset for therapeutic approaches.
ACT of Early Memory T Cells Various approaches to generate tumorreactive CD8C T cells for ACT in cancer patients have been explored. For most effective antitumor responses without severe side effects, it is imperative to target antigens that are specifically, or at least selectively, expressed by the malignant cells. These could be tumor-associated antigens, although these are generally selfpeptides with overexpression on malignant cells compared to normal tissues. Neoantigens, on the other hand, appear on tumors as a consequence of tumor-
specific mutations, and are highly immunogenic. In the setting of allogeneic stem cell transplantation (allo-SCT), donor T cells can recognize polymorphic minor histocompatibility antigens (MiHAs) expressed on patients’ malignant cells.4 Therefore, ACT using donor-derived CD8C T cells targeting MiHAs with restricted expression to the hematopoietic lineage is an attractive adjuvant therapy to prevent or treat tumor recurrence. However, the most widely explored ACT involves the isolation and ex vivo expansion of tumor-infiltrating lymphocytes (TILs). Subsequently, these tumor-reactive CD8CT cells are transferred back to the patient. An emerging strategy is to use tumor-reactive T-cell receptor (TCR)or chimeric antigen receptor (CAR)engineered T cells.5 In particular, CAR T-cell therapy has shown spectacular responses in patients with acute lymphoblastic leukemia. An alternative approach for “T-cell engineering” is the ex vivo generation of tumor-reactive CD8C T cells by expansion of their precursor cells using antigen-presenting cells (APCs), such as dendritic cells (DCs). Although various approaches are
*Correspondence to: Harry Dolstra; Email: [email protected] Submitted: 12/23/2014; Accepted: 12/23/2014 http://dx.doi.org/10.1080/2162402X.2014.1003016
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OncoImmunology
e1003016-1
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resulted in decreased tumor growth and improved survival in B16 melanoma-bearing mice. These new findings demonstrates that pharmacological inhibition of Akt represents a feasible and attractive approach to generate tumor-reactive T cells with an early memory phenotype that possess superior antitumor immunity following adoptive transfer. Upon infusion of tumor-reactive T cells, Figure 1. Strategies for the ex vivo generation of early memory tumor-reactive T cells for adoptive immunotherapy. activation and support is Generation of early memory tumor-reactive T cells via different strategies. (A, B) T-cell receptor (TCR) transfer in the essential to ensure potent presence of Wnt signaling, or interleukin (IL)-7 and IL-15 stimulation. (C) Expansion of naive T-cell progenitors using long-lasting antitumor dendritic cells in the presence of an Akt-inhibitor (Akt-inh). (D) Expansion of tumor-infiltrating lymphocytes (TILs) in responses. This could be the presence of an Akt-inhibitor. achieved via DC vaccination, using either monocyte-derived DCs being explored, all induce T-cell activa- IL-7 and IL-15 favors the expansion of or natural occurring DC subsets loaded tion resulting in differentiation into the polyclonal-stimulated TCR-engineered with the tumor antigen of interest.10 By low 7 less effective and less favorable Teff cells. CD62L T cells. Alternatively, in our transfer of tumor-specific T cells with This provides a strong rationale for recent publication, we showed that pharan early memory phenotype, in combimonitoring and inhibiting T-cell differ- macological interference with the Akt-signation with DC vaccination, an effective entiation during T-cell engineering for naling pathway during ex vivo priming antitumor response can be elicited. Proadoptive T-cell therapy. resulted in the expansion of MiHA-spemoting immunologic memory of C Gattinoni et al. showed that, by mim- cific CD8 T cells with an early tumor-reactive T-cell responses may C C 8 icking canonical Wnt-signaling, T-cell dif- CCR7 CD62L memory phenotype. improve the curative potential of cancer ferentiation can be effectively inhibited These Akt-inhibited MiHA-specific immunotherapy. Taken together, inhibiC during the generation of TCR-engineered CD8 T cells displayed effective prolifertion of T-cell differentiation (e.g., via 6 tumor-reactive T cells. Interestingly, ative capacity in vivo, and showed superior inhibiting Akt-signaling) during the these TCR-engineered Tscm-like antitumor efficacy in multiple-myelomageneration of antigen-specific T cells C C CCR7 CD62L T cells showed superior bearing mice. The superiority of Aktcould be broadly exploited for the antitumor immunity. However, a firm inhibited T cells was also reported by development of superior tumor- or inhibition in proliferation was observed Crompton et al. who showed that Akt virus-reactive stem cell-like CD8C T during culture, rendering this strategy inhibition of TILs, isolated from metacells for adoptive immunotherapy in unsuitable for ex vivo priming and expan- static melanoma patients, promotes cancer and viral infections. C C sion of CD8 T cells endogenously expansion of early CD62L memory T expressing tumor-reactive TCR, as prolif- cells with improved persistence upon Disclosure of Potential Conflicts of Interest eration is required in order to obtain suffi- adoptive transfer in immune-deficient 9 cient numbers for adoptive transfer. Cieri mice. Moreover, adoptive transfer of No potential conflicts of interest were et al. demonstrated that the presence of Akt-inhibited pmel-1 CD8C T cells disclosed. References 1. Gattinoni L, Klebanoff CA, Restifo NP. Paths to stemness: building the ultimate antitumour T cell. Nature Reviews Cancer 2012; 12: 671–84; PMID:22996603; http://dx.doi.org/10.1038/nrc3322 2. Klebanoff CA, Gattinoni L, Restifo NP. Sorting through subsets: which T-cell populations mediate highly effective adoptive immunotherapy? J Immunotherapy 2012; 35: 651–60; http://dx.doi.org/10.1097/ CJI.0b013e31827806e6
e1003016-2
3. Stemberger C, Neuenhahn M, Gebhardt FE, Schiemann M, Buchholz VR, Busch DH. Stem cell-like plasticity of naive and distinct memory CD8C T cell subsets. Semin Immunol 2009; 21: 62–8; PMID:19269852; http://dx.doi.org/10.1016/j. smim.2009.02.004 4. Bleakley M, Riddell SR. Molecules and mechanisms of the graft-versus-leukaemia effect. Nature Rev Cancer 2004; 4: 371–80; http://dx.doi.org/10.1038/nrc1365 5. June CH, Maus MV, Plesa G, Johnson LA, Zhao Y, Levine BL, Grupp SA, Porter DL. Engineered T cells
OncoImmunology
for cancer therapy. Cancer Immunol Immunother: CII 2014; 63: 969–75; http://dx.doi.org/10.1007/s00262014-1568-1 6. Gattinoni L, Lugli E, Ji Y, Pos Z, Paulos CM, Quigley MF, Almeida JR, Gostick E, Yu Z, Carpenito C, et al. A human memory T cell subset with stem cell-like properties. Nat Med 2011; 17: 1290– 7; PMID:21926977; http://dx.doi.org/10.1038/ nm.2446 7. Cieri N, Camisa B, Cocchiarella F, Forcato M, Oliveira G, Provasi E, Bondanza A, Bordignon C,
Volume 4 Issue 5
signaling promotes the generation of superior tumorreactive T cells for adoptive immunotherapy. Blood 2014; 124(23): 3490–500; PMID:25336630; http:// dx.doi.org/10.1182/blood-2014-05-578583 9. Crompton JG, Sukumar M, Roychoudhuri R, Clever D, Gros A, Eil R, Tran E, Hanada KI, Yu Z, Palmer DC, et al. Akt inhibition enhances expansion of potent tumor-specific lymphocytes with memory cell
characteristics. Cancer Res 2015; 75(2): 296–305; PMID:25432172; http://dx.doi.org/10.1158/00085472.CAN-14-2277 10. Anguille S, Smits EL, Lion E, van Tendeloo VF, Berneman ZN. Clinical use of dendritic cells for cancer therapy. Lancet Oncol 2014; 15: e257-67; PMID:24872109; http://dx.doi.org/10.1016/S14702045(13)70585-0
Downloaded by [Universite Laval] at 20:04 17 September 2015
Peccatori J, Ciceri F, et al. IL-7 and IL-15 instruct the generation of human memory stem T cells from naive precursors. Blood 2013; 121: 573–84; PMID:23160470; http://dx.doi.org/10.1182/blood2012-05-431718 8. van der Waart AB, van de Weem NM, Maas F, Kramer CS, Kester MG, Falkenburg JH, Schaap N, Jansen JH, van der Voort R, Gattinoni L, et al. Inhibition of Akt-
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OncoImmunology
e1003016-3
ISSN: (Print) 2162-402X (Online) Journal homepage: http://www.tandfonline.com/loi/koni20
Time to Akt Anniek B van der Waart, Willemijn Hobo & Harry Dolstra To cite this article: Anniek B van der Waart, Willemijn Hobo & Harry Dolstra (2015) Time to Akt, OncoImmunology, 4:5, e1003016, DOI: 10.1080/2162402X.2014.1003016 To link to this article: http://dx.doi.org/10.1080/2162402X.2014.1003016
Accepted online: 03 Feb 2015.
Submit your article to this journal
Article views: 37
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=koni20 Download by: [Universite Laval]
Date: 17 September 2015, At: 20:04
AUTHOR'S VIEW OncoImmunology 4:5, e1003016; May 2015; © 2015 Taylor & Francis Group, LLC
Time to Akt Superior tumor-reactive T cells for adoptive immunotherapy Anniek B van der Waart, Willemijn Hobo, and Harry Dolstra* Department of Laboratory Medicine - Laboratory of Hematology; Radboud university medical center; Nijmegen, The Netherlands
Keywords: adoptive T cell therapy, Akt, dendritic cell, IL-7, IL-15, stem cell transplantation, T-cell differentiation, Wnt
Downloaded by [Universite Laval] at 20:04 17 September 2015
Abbreviations: ACT: adoptive cell therapy; Allo-SCT: allogeneic stem cell transplantation; APC: antigen-presenting cells; CAR: chimeric antigen receptor; DCs: dendritic cells; MiHAs: minor histocompatibility antigens; Tcm: central memory T; TCR: T-cell receptor; Teff: effector T; Tem: effector memory T; TILs: tumor-infiltrating lymphocytes; Tn: naive T; Tscm: stem cell memory T
T cells are crucial players in the protection against cancer, and can be used in adoptive cell therapy to prevent or treat relapse. However, their state of differentiation determines their effectiveness, with early memory cells being the most favorable. Here, we discuss restraining of differentiation to engineer the ultimate tumor-reactive T cell.
T Cells with Stem Cell Flavor T cells are the soldiers of our immune system and crucial forces in the battle against solid and hematological malignancies. Adoptive cell therapy (ACT) exploiting tumor-reactive CD8C T cells is an appealing strategy to treat advanced cancer. A crucial aspect for the functionality of these CD8C T cells in antitumor immunity is their differentiation state.1,2 Upon activation of naive T (Tn) precursor cells, proliferation and differentiation is initiated into the early memory subsets, stem cell memory T (Tscm) cells, and central memory T (Tcm) cells, and their laterarising subsets—effector memory T (Tem) cells and effector T (Teff) cells.1,3 Terminally differentiated Teff cells show potent antitumor killing activity; however, most of them die after a single act of duty. In contrast, the early memory Tscm and Tcm cells not only possess stronger proliferative capacity, they are also capable of differentiating into effector T-cell subsets. Most importantly, they possess a high selfrenewal capacity, which is less profound in the more differentiated T-cell subsets. The supremacy of these early memory T
cells was demonstrated by Klebanoff et al., who described the evolvement of adoptive T-cell therapy in time.2 Using the same pmel-1 melanoma mouse model, comparable antitumor effectiveness was achieved with 500 times less Tscm cells than the “old fashioned” interleukin (IL)-2expanded Teff cells. This demonstrates the superiority of Tscm cells to fight off malignant cells, and makes early memory CD8C T cells the most favorable subset for therapeutic approaches.
ACT of Early Memory T Cells Various approaches to generate tumorreactive CD8C T cells for ACT in cancer patients have been explored. For most effective antitumor responses without severe side effects, it is imperative to target antigens that are specifically, or at least selectively, expressed by the malignant cells. These could be tumor-associated antigens, although these are generally selfpeptides with overexpression on malignant cells compared to normal tissues. Neoantigens, on the other hand, appear on tumors as a consequence of tumor-
specific mutations, and are highly immunogenic. In the setting of allogeneic stem cell transplantation (allo-SCT), donor T cells can recognize polymorphic minor histocompatibility antigens (MiHAs) expressed on patients’ malignant cells.4 Therefore, ACT using donor-derived CD8C T cells targeting MiHAs with restricted expression to the hematopoietic lineage is an attractive adjuvant therapy to prevent or treat tumor recurrence. However, the most widely explored ACT involves the isolation and ex vivo expansion of tumor-infiltrating lymphocytes (TILs). Subsequently, these tumor-reactive CD8CT cells are transferred back to the patient. An emerging strategy is to use tumor-reactive T-cell receptor (TCR)or chimeric antigen receptor (CAR)engineered T cells.5 In particular, CAR T-cell therapy has shown spectacular responses in patients with acute lymphoblastic leukemia. An alternative approach for “T-cell engineering” is the ex vivo generation of tumor-reactive CD8C T cells by expansion of their precursor cells using antigen-presenting cells (APCs), such as dendritic cells (DCs). Although various approaches are
*Correspondence to: Harry Dolstra; Email: [email protected] Submitted: 12/23/2014; Accepted: 12/23/2014 http://dx.doi.org/10.1080/2162402X.2014.1003016
www.tandfonline.com
OncoImmunology
e1003016-1
Downloaded by [Universite Laval] at 20:04 17 September 2015
resulted in decreased tumor growth and improved survival in B16 melanoma-bearing mice. These new findings demonstrates that pharmacological inhibition of Akt represents a feasible and attractive approach to generate tumor-reactive T cells with an early memory phenotype that possess superior antitumor immunity following adoptive transfer. Upon infusion of tumor-reactive T cells, Figure 1. Strategies for the ex vivo generation of early memory tumor-reactive T cells for adoptive immunotherapy. activation and support is Generation of early memory tumor-reactive T cells via different strategies. (A, B) T-cell receptor (TCR) transfer in the essential to ensure potent presence of Wnt signaling, or interleukin (IL)-7 and IL-15 stimulation. (C) Expansion of naive T-cell progenitors using long-lasting antitumor dendritic cells in the presence of an Akt-inhibitor (Akt-inh). (D) Expansion of tumor-infiltrating lymphocytes (TILs) in responses. This could be the presence of an Akt-inhibitor. achieved via DC vaccination, using either monocyte-derived DCs being explored, all induce T-cell activa- IL-7 and IL-15 favors the expansion of or natural occurring DC subsets loaded tion resulting in differentiation into the polyclonal-stimulated TCR-engineered with the tumor antigen of interest.10 By low 7 less effective and less favorable Teff cells. CD62L T cells. Alternatively, in our transfer of tumor-specific T cells with This provides a strong rationale for recent publication, we showed that pharan early memory phenotype, in combimonitoring and inhibiting T-cell differ- macological interference with the Akt-signation with DC vaccination, an effective entiation during T-cell engineering for naling pathway during ex vivo priming antitumor response can be elicited. Proadoptive T-cell therapy. resulted in the expansion of MiHA-spemoting immunologic memory of C Gattinoni et al. showed that, by mim- cific CD8 T cells with an early tumor-reactive T-cell responses may C C 8 icking canonical Wnt-signaling, T-cell dif- CCR7 CD62L memory phenotype. improve the curative potential of cancer ferentiation can be effectively inhibited These Akt-inhibited MiHA-specific immunotherapy. Taken together, inhibiC during the generation of TCR-engineered CD8 T cells displayed effective prolifertion of T-cell differentiation (e.g., via 6 tumor-reactive T cells. Interestingly, ative capacity in vivo, and showed superior inhibiting Akt-signaling) during the these TCR-engineered Tscm-like antitumor efficacy in multiple-myelomageneration of antigen-specific T cells C C CCR7 CD62L T cells showed superior bearing mice. The superiority of Aktcould be broadly exploited for the antitumor immunity. However, a firm inhibited T cells was also reported by development of superior tumor- or inhibition in proliferation was observed Crompton et al. who showed that Akt virus-reactive stem cell-like CD8C T during culture, rendering this strategy inhibition of TILs, isolated from metacells for adoptive immunotherapy in unsuitable for ex vivo priming and expan- static melanoma patients, promotes cancer and viral infections. C C sion of CD8 T cells endogenously expansion of early CD62L memory T expressing tumor-reactive TCR, as prolif- cells with improved persistence upon Disclosure of Potential Conflicts of Interest eration is required in order to obtain suffi- adoptive transfer in immune-deficient 9 cient numbers for adoptive transfer. Cieri mice. Moreover, adoptive transfer of No potential conflicts of interest were et al. demonstrated that the presence of Akt-inhibited pmel-1 CD8C T cells disclosed. References 1. Gattinoni L, Klebanoff CA, Restifo NP. Paths to stemness: building the ultimate antitumour T cell. Nature Reviews Cancer 2012; 12: 671–84; PMID:22996603; http://dx.doi.org/10.1038/nrc3322 2. Klebanoff CA, Gattinoni L, Restifo NP. Sorting through subsets: which T-cell populations mediate highly effective adoptive immunotherapy? J Immunotherapy 2012; 35: 651–60; http://dx.doi.org/10.1097/ CJI.0b013e31827806e6
e1003016-2
3. Stemberger C, Neuenhahn M, Gebhardt FE, Schiemann M, Buchholz VR, Busch DH. Stem cell-like plasticity of naive and distinct memory CD8C T cell subsets. Semin Immunol 2009; 21: 62–8; PMID:19269852; http://dx.doi.org/10.1016/j. smim.2009.02.004 4. Bleakley M, Riddell SR. Molecules and mechanisms of the graft-versus-leukaemia effect. Nature Rev Cancer 2004; 4: 371–80; http://dx.doi.org/10.1038/nrc1365 5. June CH, Maus MV, Plesa G, Johnson LA, Zhao Y, Levine BL, Grupp SA, Porter DL. Engineered T cells
OncoImmunology
for cancer therapy. Cancer Immunol Immunother: CII 2014; 63: 969–75; http://dx.doi.org/10.1007/s00262014-1568-1 6. Gattinoni L, Lugli E, Ji Y, Pos Z, Paulos CM, Quigley MF, Almeida JR, Gostick E, Yu Z, Carpenito C, et al. A human memory T cell subset with stem cell-like properties. Nat Med 2011; 17: 1290– 7; PMID:21926977; http://dx.doi.org/10.1038/ nm.2446 7. Cieri N, Camisa B, Cocchiarella F, Forcato M, Oliveira G, Provasi E, Bondanza A, Bordignon C,
Volume 4 Issue 5
signaling promotes the generation of superior tumorreactive T cells for adoptive immunotherapy. Blood 2014; 124(23): 3490–500; PMID:25336630; http:// dx.doi.org/10.1182/blood-2014-05-578583 9. Crompton JG, Sukumar M, Roychoudhuri R, Clever D, Gros A, Eil R, Tran E, Hanada KI, Yu Z, Palmer DC, et al. Akt inhibition enhances expansion of potent tumor-specific lymphocytes with memory cell
characteristics. Cancer Res 2015; 75(2): 296–305; PMID:25432172; http://dx.doi.org/10.1158/00085472.CAN-14-2277 10. Anguille S, Smits EL, Lion E, van Tendeloo VF, Berneman ZN. Clinical use of dendritic cells for cancer therapy. Lancet Oncol 2014; 15: e257-67; PMID:24872109; http://dx.doi.org/10.1016/S14702045(13)70585-0
Downloaded by [Universite Laval] at 20:04 17 September 2015
Peccatori J, Ciceri F, et al. IL-7 and IL-15 instruct the generation of human memory stem T cells from naive precursors. Blood 2013; 121: 573–84; PMID:23160470; http://dx.doi.org/10.1182/blood2012-05-431718 8. van der Waart AB, van de Weem NM, Maas F, Kramer CS, Kester MG, Falkenburg JH, Schaap N, Jansen JH, van der Voort R, Gattinoni L, et al. Inhibition of Akt-
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OncoImmunology
e1003016-3
