Chimeric Antigen Receptor– and TCR-Modified T Cells Enter Main Street and Wall Street

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and TCR-Modified T Cells Enter Main Street and

?Chimeric Antigen Receptor David M. Barrett, Stephan A. Grupp and Carl H. June https://www.360docs.net/doc/d810907127.html,/content/195/3/755

doi: 10.4049/jimmunol.1500751

2015; 195:755-761; ;J Immunol References https://www.360docs.net/doc/d810907127.html,/content/195/3/755.full#ref-list-1

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Chimeric Antigen Receptor–and TCR-Modi?ed T Cells Enter Main Street and Wall Street

David M.Barrett,*Stephan A.Grupp,*,?and Carl H.June?,?

The?eld of adoptive cell transfer(ACT)is currently comprised of chimeric Ag receptor(CAR)–and TCR-engineered T cells and has emerged from principles of basic immunology to paradigm-shifting clinical immunotherapy.ACT of T cells engineered to express arti?cial receptors that target cells of choice is an ex-citing new approach for cancer,and it holds equal promise for chronic infection and https://www.360docs.net/doc/d810907127.html,-ing principles of synthetic biology,advances in immu-nology,and genetic engineering have made it possible to generate human T cells that display desired speci?c-ities and enhanced functionalities.Clinical trials in patients with advanced B cell leukemias and lympho-mas treated with CD19-speci?c CAR T cells have in-duced durable remissions in adults and children.The prospects for the widespread availability of engineered T cells have changed dramatically given the recent en-try of the pharmaceutical industry to this arena.In this overview,we discuss some of the challenges and oppor-tunities that face the?eld of ACT.The Journal of Immunology,2015,195:755–761.

P resently there are three types of adoptive cell transfer (ACT)using effector T cells that are advancing on

a path toward regulatory approval(Fig.1).Tumor-in?ltrating lymphocytes(TILs)have been developed with slow but continuing progress during several decades.Recently, an international phase III randomized trial has begun for patients with metastatic melanoma.Lion Biotechnologies has been formed to commercialize TIL therapies for melanoma and other tumors that have suitable T cell in?ltration.

In contrast to TILs,gene transfer–based strategies have been developed to overcome the consequences of immune tolerance on the tumor-speci?c T cell repertoire.These approaches provide the potential to ef?ciently redirect T cells to tissues by transferring chimeric Ag receptors(CARs)composed of Ab-binding domains fused to T cell signaling domains,or by transferring cells expressing TCR a/b heterodimers.The infusion of gene-modi?ed T cells directed to speci?c targets offers the possibility to endow the immune system with reactivities that are not naturally present.This approach has the additional bene?t of rapid tumor eradication that is usually

seen with cytotoxic chemotherapy or with targeted therapies,

and it contrasts to the delayed effects that are usually observed with vaccines and T cell checkpoint therapies.

Cell therapies are ultimately personalized in that,with rare exceptions,they are comprised of autologous,patient-derived

T cells.For this reason,ACT is primarily being developed

based on an unprecedented reliance on academic and phar-maceutical industry partnerships.In this model,academia and

industry are coexisting,with the former developing and testing

new ideas regarding cellular engineering and the latter scaling to achieve global impact on health care.Such academic and

industrial partnerships have recently emerged at numerous

institutions worldwide,including the University of Pennsyl-vania with Novartis,Baylor College of Medicine with Blue-

bird Bio and Celgene,the Memorial Sloan Kettering Cancer

Center and the Fred Hutchinson Cancer Research Center with Juno Therapeutics,the National Cancer Institute with

Kite Pharma,and the Cellular Biomedicine Group with the

Chinese PLA General Hospital.Overall,there are now dozens of companies in the cell therapy?eld representing billions of

dollars in investments(1).The in?uence of these partnerships

remains uncertain,as the merger of academic intellectual freedom with the big business focus on value will surely create

con?ict.Pursuit of extramural grant funding and the rights to

intellectual property will be intense topics of conversation between academic investigators,who created this?eld,and

the pharmaceutical companies that seek to license the science. Potential roles of ACT in HIV-1infection and other chronic infections.It is interesting to note from a historical perspec-tive that some of the?rst forms of ACT involving gene-

modi?ed T cells were conducted almost two decades ago in patients with advanced HIV-1/AIDS(2),and that many of

the results from trials conducted in HIV-1–infected patients

have informed current concepts in the?eld of cancer,as exempli?ed by the demonstration that CAR T cells could

survive for more than a decade in HIV-1/AIDS patients(3).

These initial trials were done to control drug-resistant forms of HIV-1infection.However,the current challenge in the ?eld is to develop cellular therapies with the potential to

*Division of Oncology,Department of Pediatrics,Children’s Hospital of Philadelphia, Philadelphia,PA19104;?Department of Pathology and Laboratory Medicine,Perelman School of Medicine,University of Pennsylvania,Philadelphia,PA19104;and?Center for Cellular Immunotherapies,Perelman School of Medicine,University of Pennsylva-nia,Philadelphia,PA19104

ORCID:0000-0003-0241-3557(C.H.J.).

Received for publication April1,2015.Accepted for publication June1,2015.Address correspondence and reprint requests to Prof.Carl H.June,University of Penn-sylvania,3400Civic Center Boulevard,Building421,Philadelphia,PA19104-5156. E-mail address:cjune@https://www.360docs.net/doc/d810907127.html,

Abbreviations used in this article:ACT,adoptive cell transfer;ALL,acute lymphoblastic leukemia;CAR,chimeric Ag receptor;CRS,cytokine release syndrome;TIL,tumor-in?ltrating lymphocyte;Treg,regulatory T cell.

Copyrightó2015by The American Association of Immunologists,Inc.0022-1767/15/$25.00

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eliminate the reservoir of HIV-1that is resistant to current antiviral therapies (4).The ?eld has been energized by an extraordinary experiment conducted by Gero H €u tter et al.(5)in Berlin in a patient who has apparently been cured of HIV-1infection following an allogeneic hematopoietic stem cell transplant and ACT from an HIV-12homozygous CCR5Delta32donor.There are a number of approaches to induce a cell-intrinsic resistance to HIV-1infection and to target the reservoir of HIV-1by gene-modi?ed ACT (6).Recent studies suggest that ACT with appropriately targeted CD8+CTLs can clear HIV-1latent reservoirs in humanized mice (7),providing additional rationale for the application of ACT using genetically modi?ed T cells for the therapy of HIV-1infection and other chronic infections that often fail to be controlled by the endogenous immune system.It is likely that the incremental improvements in the construction of mice with humanized immune systems will greatly accelerate the development of successful ACT for HIV-1infection.

Engineering regulatory T cells.There is increasing interest in harnessing regulatory T cells (Tregs)to downregulate unwanted immune responses.The ef?cacy of this approach has been shown in preclinical models of autoimmune disease and allograft rejection,as the adoptive transfer of Tregs can prevent lethal graft-versus-host disease and autoimmune diabetes in mice (8,9).The adoptive transfer of expanded cord blood Tregs has been shown to be safe and feasible in patients undergoing allogeneic hematopoietic stem cell transplantation (10).Distinct cell culture methodologies have been developed to optimize the expansion and function of natural and induced Tregs (11,12).The need for differential cell culture approaches is likely due to differences in signal transduction between Tregs and effector T cells (13).The principles of synthetic engineering have been applied to Tregs;for example,CAR Tregs show promise in preclinical models of autoimmunity (14,15).The concept of using a CAR in Tregs is centered around directing Tregs to a vulnerable tissue via the CAR,where their engagement would result in suppression of autoimmunity.Speci?cally,modifying mouse Tregs with a CAR targeting myelin basic protein–speci?c T cells protected against autoimmune encephalitis,and the concept is being pursued for colitis-and diabetes-targeting Ags in the colon and pancreatic islet,respectively (16–18).

Role of animal modeling for ACT.Animal models have played

a key role in developing cellular therapies.There are two major variations used by investigators:the syngeneic mouse model using mouse T cells and mouse Ags,and the xenograft model using immunode?cient mice and human T cells and tumor cells (19,20).During the decades of development of cellular therapies,these models have produced often contradictory and con?icting conclusions (20,21).The considerable number of variables involved in producing a cellular therapy is one of the factors behind such results.The structure of the CAR,the cellular composition of the T cells (CD4/CD8or both),the choice of costimulatory domain,the method of gene transfer,the method and time of ex vivo expansion,the use or not of lymphodepleted hosts,and the amount and type of tumor burden must all be controlled to draw accurate conclusions.As one example,the use of the CD28costimulatory domain in the CAR structure was found to be bene?cial in a xenograft model that did not use CD28stimulation in the ex vivo expansion (22).

The syngeneic mouse model has the inherent bene?t of modeling an intact immune system,whereas the xenograft system has the advantage of allowing the study of human cells.Xenograft systems have accurately predicted ef?cacy in several reports studying chimeric Ag receptors (23–25).These systems failed to predict any of the toxicity,speci?cally the cytokine release syndrome (CRS)described in pediatric acute lym-phoblastic leukemia (ALL)treated with anti-CD19CAR T cells (see below)(26,27).Syngeneic mouse models have not yet mimicked the CRS,although they have predicted some ef?cacy (28–30).In part,this is due to subtle yet im-portant differences in the ability to ex vivo stimulate and expand T cells of human or murine origin.As clinical trials are obviously focused on human T cells,the understanding of in?uences of human T cell costimulation are of paramount importance and support the utility of the xenograft model.More sophisticated models using humanized mice such as the MISTRG strain (immunode?cient mice with transgenic ex-pression of human cytokines such as GM-CSF,M-CSF,IL-3,and thrombopoietin)provide species-speci?c cytokine sup-port for human cells,allow for improved engraftment of some such cells,and may allow for modeling both ef?cacy and toxicity with human cells (31).Additional hybrid models

such

FIGURE 1.Cellular therapy has several pathways to the patient.Normal donor cells can be modi?ed to inactivate their alloreactivity while being armed with antitumor CARs or TCRs,or a patient’s own cells can be modi?ed with antitumor molecules.In the case of solid tumors,biopsy specimens can be used to isolate TILs for expan-sion.In most cases the patient will require some amount of conditioning before receiving antitumor lymphocyte infusions,and careful management of toxicities emerging from these therapies is also required.

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as the SCID/beige mouse with human T cells interacting with mouse monocyte lineages may provide additional insights (32).A truly ef?cacious syngeneic mouse model,however,is likely to provide less confounding results than arti?cially hu-manized mice but still requires more development to improve on the actionable data generated by present xenograft models.Thus,syngeneic and humanized xenograft mouse models provide complementary insights,with syngeneic systems being most suited to probe murine cell biology with an intact im-mune cell milieu,whereas humanized systems allow for human cell engraftment and in vivo human cell–cell interaction.

Uncovering the optimal CAR design.CAR design has progressed during the past two decades (Fig.2).Three laboratories re-ported the ?rst generation CAR design in 1991(33–35).Kuwana et al.(36)?rst created a chimeric receptor that resulted in MHC class I–independent T cell recognition.Roberts (37)and Finney and Lawson (38)designed the ?rst second generation CARs encoding CD28or 4-1BB signaling domains.In preclinical models,others found that 4-1BB but not CD28provided advantages to CAR ef?cacy in a xenograft model,but used a CD28-based ex vivo expansion system (25,39).Both CAR models showed preclinical ef?cacy,and both have demonstrated clinical ef?cacy (26,27,40).Recent studies by Long et al.(41)indicate that CD28-based CARs augment and accelerate T cell exhaustion,whereas 4-1BB–based CARs reduce T cell exhaustion.Our own studies agree with these ?ndings and indicate that CD28-based endodomains can mediate constitutive signaling leading to terminal differentiation of effector T cells (42).The careful conclusion from these studies is not that one human endodomain is necessarily better than the other,but rather that the CD28signal is key in producing effective clinical T cell products,and that 4-1BB promotes persistence of CAR T cells.Perspective on toxicity from ACT.For more than a decade,many clinical trials using ACT had shown a variety of engineered cell products to be quite safe,but relatively nonef?cacious.In the past 4y,ACT has undergone a revolution in ef?cacy,which re?ects that T cells can now be manufactured in such a way as to allow extensive in vivo proliferation (40,43,44)and even,in some cases,long-term persistence (3,27).This has radically changed the ef?cacy of ACT,especially in the area of CAR T cells,but as is so often the case in cancer therapy,with ef?cacy comes toxicity.Cytokine release syndrome.The most prominent toxicity of CAR T cells for bone marrow–derived tumors is CRS.Highly proliferative T cells can produce CRS,which may range from high fever and myalgias to unstable hypotension and respi-ratory failure.This was an unexpected observation because it was not observed in preclinical animal models.A key insight into CRS came with the observation that,in addition to the expected effector cytokines such as IFN-g ,IL-6can be quite elevated during the exponential proliferative phase of CAR T cell therapy (27).CRS is directly and possibly causally re-lated to a complementary toxicity,which is macrophage ac-tivation syndrome (26).Fortunately,these insights have also resulted in a therapeutic option for severe CRS,which is IL-6blockade using the IL-6receptor antagonist tocilizumab.Several of the groups treating ALL with highly proliferative CAR T cells have con?rmed both the IL-6observation and the ef?cacy of tocilizumab for severe CRS (40,45,46),and we have observed a similar mechanism underlying severe CRS driven by the bispeci?c T cell–engaging Ab blinatumomab (47).Another important observation is that severe CRS is observed almost exclusively in patients with high disease burden (27).This means that as CAR T cells are deployed in patients earlier in the course of their disease,before the disease becomes refractory to cytoreduction prior to CAR infusion,the risk of severe CRS will be far lower.

On-target toxicity.CRS is a direct result of T cell prolif-eration.It is not dependent on the antigenic speci?city of the engineered T cell,although there may be differences in CRS risk and symptoms depending on the disease being treated,even where the CAR is the same.For example,CRS is generally milder in CLL and diffuse large B cell lymphoma and more prominent in ALL.In addition to CRS,there are toxicities that are described as “on target”because they di-rectly result from the antigenic speci?city of the engineered T cell.Examples of this include tumor lysis syndrome,which is a direct result of tumor cell destruction (43,48).B cell aplasia is an on-target but off-tissue toxicity,which is seen with CARs directed to B cell–expressed targets such as CD19.Because B cell aplasia is present as long as CD19CAR T cells are present,absence of B cells serves as a useful pharmacodynamic marker of CAR T cell functional persis-tence (27).B cell aplasia produces a more profound hypo-gammaglobulinemia compared with patients infused with anti-CD20–speci?c mAbs,which must be treated with i.v.

Ig

FIGURE 2.Design of CAR T cells.First-generation CARs incorporated the CD3z -chain or similar signaling domains.Ab-based redirection of T cells was ?rst de-scribed by Kuwana and re?ned by Eshhar.Roberts and Finney ?rst described second-generation CARs incorporating CD28or CD137signaling domains.

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replacement.Unlike the relative hypogammaglobulinemia seen with the anti-CD20Ab rituximab,i.v.Ig replacement is absolutely required during prolonged CAR-mediated B cell aplasia.Two recent case reports of lethal toxicities related to engineered T cell infusion described a patient who received a Her-2CAR (49)and two patients infused with an engi-neered TCR targeting MAGE-A3(50,51).In both cases,off-cancer expression of the target in normal tissues resulted in rapid and overwhelming cardiopulmonary toxicity.All of these on-target toxicities result from the inability of engi-neered T cells to distinguish between normal cells and cancer cells that express the targeted Ag.The toxicity from high-af?nity TCR-engineered T cells may be a result of the af-?nity maturation process,as the “on target off tumor”aspect may be restricted to the high-af?nity TCR that would not have happened physiologically.Careful screening of high-af?nity TCRs will be needed to address the possibility of recognizing epitopes outside of the target protein as a result of high-af?nity design process.Neurologic toxicity has also been reported after infusion of T cells engineered with an HLA-A2–restricted MAGE-A3–speci?c TCR (52).

Neurologic toxicities.A further unexpected and as yet un-explained phenomenon seen with CAR T cell therapy against leukemia is the emergence of neurologic symptoms.Reported by several groups,these symptoms are varied but self-limiting,including delirium,dysphasia,akinetic mutism,and seizures (26,27,40,45,53).Although somewhat temporally related to the systemic CRS and certainly correlated with the presence of CAR cells in the cerebrospinal ?uid,these symptoms do not appear to be modi?ed by tocilizumab.The mechanism and target tissues of these symptoms remain to be determined.Other toxicities.Infusion of activated T cells carries the risk of autoimmunity.Vitiligo is seen with melanoma-directed ACT,and toxicities such as rash,colitis,and hypophysitis have been described rarely with activated T cell infusions (54,55).This has not been a signi?cant issue with CAR-modi?ed T cells.When allogeneic T cells are used for the infusion,there is a potential risk of graft-versus-host disease.This might be a concern in patients who have previously undergone alloge-neic stem cell transplant.Fortunately,the approach of col-lecting tolerized donor-origin T cells from the recipient (rather than going back to the donor)appears to have a very low risk of graft-versus-host disease (27).Certainly,one ap-proach to limiting toxicity would be the use of suicide systems such as the elegant inducible caspase-9system or the inclusion of de?ned surface targets such as CD20(56).In the case of inducible caspase-9,a soluble activating agent causes the in-duction of the caspase system,resulting in apoptosis of the T cells.By including CD20in the gene modi?cation of the CAR T cells,a mAb such as rituximab could be used to clear the offending T cells.

Current issues facing the ?eld.At present there are a number of scienti?c and engineering challenges that are being addressed in the laboratory.Below we address some of the current challenges.

Composition of the cell product.Initial cell therapies were primarily administered as highly differentiated CD8+T cells.These CTLs cells had optimal cytotoxicity but did not have suf?cient replicative capacity after infusion,and,with rare exceptions,the infused T cell products had poor persistence in the patients.It is now widely accepted that

mixtures of CD4+and CD8+T cells are often preferred,likely because the CD4+T cells provide growth factors and other signals to maintain function and survival of the in-fused CTLs.Additionally,studies in mice sometimes mis-lead approaches with human T cells.For instance,human T cells have limitations on replicative capacity by virtue of telomere degradation,a feature not encountered in mouse models,and human CD4cells can exhibit more cytotoxicity than do mouse CD4cells (57,58).At issue is whether to separate subpopulations of cells from patients by ?ow cytometry or other methods and culture them indepen-dently.The optimal cell culture conditions for CD4cells and CD8cells are distinct,in part because the signal transduction pathways differ in CD4+and CD8+T cells (59).Additionally,cell separation approaches enable the removal of Tregs that are potentially harmful for therapies using effector T cells.Furthermore,tumor cells may need to be removed from the input T cells,an issue that is particularly challenging in patients with leukemia.However,the cost of cell manufacturing weighs heavily on the technologies used in good manufacturing practices,as cell sorting by ?ow cytometry or bead-based approaches can easily add $10,000or more to the cost of goods for the infused product.

Young or old?Related to the above issue,what is the optimal state of differentiation of the infused T cells?Studies in mice and humans now indicate that naive or central memory cells are preferable (60,61).A challenge is how to enable this approach in elderly adults who may have very few naive T cells,a condition often aggravated by chemotherapy or other disease processes.Our data in leukemia patients treated with CD19-speci?c CARs indicate that replicative ca-pacity is the most important predictive biomarker of success (48,62).One approach is to isolate central memory or naive T cells from input lymphocytes obtained from whole blood.In contrast,a more robust and simple approach has been to use bulk T cells and then to culture the T cells under conditions that promote the maintenance of a less differentiated pop-ulation of naive and central memory cells.This later approach is based on principles that speci?c costimulatory signals can promote selected fate and differentiation.For instance,CD28stimulation can program CD4cells to maintain central memory states (63,64),and 4-1BB promotes the growth of CD8central memory cells (65).In contrast,ICOS cosignal-ing can promote the outgrowth and stability of Th17cells (66).The use of T cells with stem cell–like qualities is promising (67,68),and enforced Wnt signaling promotes the propagation of memory stem cells (69).

Is there a uniform and optimal formulation of the ?nal cell product or does it vary for different cancers?It is unknown as to whether the striking and unexpected success of CD19CAR T cells for the treatment of B cell malignancies can be recapitulated in patients with solid tumors.We ?nd that CAR T cells can kill primary adenocarcinoma cells in vitro with an ef?ciency that is similar to leukemia targets.However,it remains to be determined whether the cell composition or the cell culture conditions will require modi?cation to optimize traf?cking and persistence of engineered T cells for patients with solid tumors.It is likely that the cell engineering to optimize traf?cking of T cells to tumors that are compart-mented,such as glioblastoma and pancreatic cancer,rather than disseminated as in hematologic malignancies,may differ.

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One approach that has been proposed is the use of targeting strategies such as genetically engineering various chemokines or chemokine receptors to promote homing of the infused T cells to tumor deposits (70,71).Other approaches include pre-conditioning the tumor or the host with radiation (72–75),the injection of oncolytic vectors (76),and the direct intra-tumoral injection of the T cells (77).

Are optimal costimulatory domains the same in CD4+and CD8+T cell subsets?Previous studies have shown that the optimal culture conditions for various T cell subsets are dis-tinct (65,78).This raises the related question as to whether various lymphocyte subsets of engineered T cells should be equipped with distinct signaling domains?To begin to address this issue we have assessed the use of endodomains comprised of CD28,4-1BB,and ICOS in human CD4+and CD8+T cells.In humanized mice bearing adenocarcinoma xenografts,we ?nd that CD4+CAR T cells equipped with an ICOS signaling domain are superior,whereas 4-1BB domains are generally pre-ferred in CD8+T cells (79).It remains to be determined whether the bene?ts derived from the increased complexity of cell manufacturing will be justi?ed in clinical scenarios.Furthermore,it is likely that the optimal composition of the T cell subsets and engineered signaling domains will differ for various tumor microenvironments.For instance,engineered Th17cells are pre-ferable to Th1cells in some preclinical tumor models (80).To be or not to be:will suicide constructs enable attenu-ation of off-tumor toxicities?Perhaps the largest uncertainty with the use of engineered T cells is whether biosynthetic engi-neering to induce novel speci?cities and enhanced effector functions will result in unexpected off-target toxicities.This is a signi?cant concern because on-target but off-tumor toxicity has occurred with CAR T cells (49,81),and off-target toxicity has occurred with TCR-engineered T cells (50,51).There are various approaches to mitigate these events.We have found that transfecting T cells with mRNA encoding the CAR to provide self-limited expression of the CAR in transferred T cells is useful to screen for immediate tox-icities,and that with emergence of toxicity,it will rapidly abate when the infusions are terminated (82,83).Various approaches to induce apoptosis of genetically modi?ed T cells have been pro-posed (84,85),and it is likely that these approaches will be in-corporated so that enhanced effector functions can be matched with conditional ablation to achieve stringent safety requirements.

Conclusions

Based on ongoing trials,synthetic T cells expressing engineered CARs and TCRs are poised to gain widespread commercial ap-proval.The resources of Wall Street are now fueling advances that were previously limited due to insuf?cient investment in this ?eld.The ability to introduce or delete genes in infused T cells (86,87)has the additional potential to provide novel cell products to overcome the immunosuppression in the tumor microenviron-ments and may ultimately eliminate the need for checkpoint therapy using systemic Ab blockade (88).It is likely that the advent of advanced genetic engineering technologies for ACT will enable signi?cant progress in applying the principles of synthetic biology to cancer therapy,chronic infections,and autoimmunity.

Disclosures

S.A.G.and C.H.J.have intellectual property with engineered T cells that is owned by the University of Pennsylvania and has been licensed to Novartis.D.M.B.has no ?nancial con?icts of interest.

References

1.June,C.H.,S.R.Riddell,and T.N.Schumacher.2015.Adoptive cellular therapy:a race to the ?nish line.Sci.Transl.Med.7:280ps7.

2.Riddell,S.R.,M.Elliott,D.A.Lewinsohn,M.J.Gilbert,L.Wilson,S.A.Manley,S.D.Lupton,R.W.Overell,T.C.Reynolds,L.Corey,and P.D.Greenberg.1996.T-cell mediated rejection of gene-modi?ed HIV-speci?c cytotoxic T lymphocytes in HIV-infected patients.Nat.Med.2:216–22

3.

3.Scholler,J.,T.Brady,G.Binder-Scholl,W.-T.Hwang,G.Plesa,K.Hege,A.Vogel,M.Kalos,J.Riley,S.Deeks,et al.2012.Decade-long safety and function of retroviral-modi?ed chimeric antigen receptor T cells.Sci.Transl.Med.4:132ra153.

4.Ho,Y.C.,L.Shan,N.N.Hosmane,J.Wang,https://www.360docs.net/doc/d810907127.html,skey,D.I.Rosenbloom,https://www.360docs.net/doc/d810907127.html,i,J.N.Blankson,J.D.Siliciano,and R.F.Siliciano.2013.Replication-competent noninduced proviruses in the latent reservoir increase barrier to HIV-1cure.Cell 155:540–551.

5.H €u tter,G.,D.Nowak,M.Mossner,S.Ganepola,A.M €u ssig,K.Allers,T.Schneider,J.Hofmann,C.K €u cherer,O.Blau,et al.2009.Long-term control of HIV by CCR5Delta32/Delta32stem-cell transplantation.N.Engl.J.Med.360:692–698.

6.Rossi,J.J.,C.H.June,and D.B.Kohn.200

7.Genetic therapies against HIV.Nat.Biotechnol.25:1444–1454.

7.Deng,K.,M.Pertea,A.Rongvaux,L.Wang,C.M.Durand,G.Ghiaur,https://www.360docs.net/doc/d810907127.html,i,H.L.McHugh,H.Hao,H.Zhang,et al.2015.Broad CTL response is required to clear latent HIV-1due to dominance of escape mutations.Nature 517:381–385.8.Taylor,P.A.,C.J.Lees,and B.R.Blazar.2002.The infusion of ex vivo activated and expanded CD4+CD25+immune regulatory cells inhibits graft-versus-host dis-ease lethality.Blood 99:3493–3499.

9.Tang,Q.,K.J.Henriksen,M.Bi,E.B.Finger,G.Szot,J.Ye,E.L.Masteller,H.McDevitt,M.Bonyhadi,and J.A.Bluestone.2004.In vitro-expanded antigen-speci?c regulatory T cells suppress autoimmune diabetes.J.Exp.Med.199:1455–1465.10.Brunstein, C.G.,https://www.360docs.net/doc/d810907127.html,ler,Q.Cao, D.H.McKenna,K.L.Hippen,

J.Curtsinger,T.Defor,B.L.Levine,C.H.June,P.Rubinstein,et al.2011.In-fusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood:safety pro?le and detection kinetics.Blood 117:1061–1070.

11.Hippen,K.L.,S. C.Merkel, D.K.Schirm, C.M.Sieben, D.Sumstad,

D.M.Kadidlo,D.H.McKenna,J.S.Bromberg,B.L.Levine,J.L.Riley,et al.2011.Massive ex vivo expansion of human natural regulatory T cells (T regs )with minimal loss of in vivo functional activity.Sci.Transl.Med.3:83ra41.

12.Hippen,K.L.,S.C.Merkel,D.K.Schirm,C.Nelson,N.C.Tennis,J.L.Riley,

C.H.June,https://www.360docs.net/doc/d810907127.html,ler,J.E.Wagner,and B.R.Blazar.2011.Generation and large-scale expansion of human inducible regulatory T cells that suppress graft-versus-host disease.Am.J.Transplant.11:1148–1157.

13.Zanin-Zhorov,A.,Y.Ding,S.Kumari,M.Attur,K.L.Hippen,M.Brown,

B.R.Blazar,S.B.Abramson,https://www.360docs.net/doc/d810907127.html,faille,and M.L.Dustin.2010.Protein kinase C-u mediates negative feedback on regulatory T cell function.Science 328:372–376.14.Mekala,D.J.,and T.L.Geiger.2005.Immunotherapy of autoimmune encepha-lomyelitis with redirected CD4+CD25+T lymphocytes.Blood 105:2090–2092.15.Moisini,I.,P.Nguyen,L.Fugger,and T.L.Geiger.2008.Redirecting therapeutic

T cells against myelin-speci?c T lymphocytes using a humanized myelin basic protein-HLA-DR2-z chimeric receptor.J.Immunol.180:3601–3611.

16.Riley,J.L.,C.H.June,and B.R.Blazar.2009.Human T regulatory cell therapy:

take a billion or so and call me in the morning.Immunity 30:656–665.

17.Esensten,J.H.,D.Wofsy,and J.A.Bluestone.2009.Regulatory T cells as ther-apeutic targets in rheumatoid arthritis.Nat Rev Rheumatol 5:560–565.

18.Jethwa,H.,A.A.Adami,and https://www.360docs.net/doc/d810907127.html,e of gene-modi?ed regulatory

T-cells to control autoimmune and alloimmune pathology:is now the right time?Clin.Immunol.150:51–63.

19.Hwu,P.,J.C.Yang,R.Cowherd,J.Treisman,G.E.Shafer,Z.Eshhar,and

S.A.Rosenberg.1995.In vivo antitumor activity of T cells redirected with chimeric antibody/T-cell receptor genes.Cancer Res.55:3369–3373.

20.Barrett,D.M.,N.Singh,X.Liu,S.Jiang,C.H.June,S.A.Grupp,and Y.Zhao.

2014.Relation of clinical culture method to T-cell memory status and ef?cacy in xenograft models of adoptive immunotherapy.Cytotherapy 16:619–630.

21.Barrett,D.M.,N.Singh,D.L.Porter,S.A.Grupp,and C.H.June.2014.

Chimeric antigen receptor therapy for cancer.Annu.Rev.Med.65:333–347.22.Brentjens,R.J.,E.Santos,Y.Nikhamin,R.Yeh,M.Matsushita,https://www.360docs.net/doc/d810907127.html, Perle,

A.Quinta

′s-Cardama,https://www.360docs.net/doc/d810907127.html,rson,and M.Sadelain.2007.Genetically targeted T cells eradicate systemic acute lymphoblastic leukemia xenografts.Clin.Cancer Res.13:5426–5435.

23.Lee,J.C.,E.Hayman,H.J.Pegram,E.Santos,G.Heller,M.Sadelain,and

R.Brentjens.2011.In vivo inhibition of human CD19-targeted effector T cells by natural T regulatory cells in a xenotransplant murine model of B cell malignancy.Cancer Res.71:2871–2881.

24.Mardiros,A.,C.Dos Santos,T.McDonald,C.E.Brown,X.Wang,L.E.Budde,

L.Hoffman, B.Aguilar,W. C.Chang,W.Bretzlaff,et al.2013.T cells expressing CD123-speci?c chimeric antigen receptors exhibit speci?c cytolytic effector functions and antitumor effects against human acute myeloid leukemia.Blood 122:3138–3148.

https://www.360docs.net/doc/d810907127.html,one,M.C.,J.D.Fish,C.Carpenito,R.G.Carroll,G.K.Binder,D.Teachey,

M.Samanta,https://www.360docs.net/doc/d810907127.html,khal,B.Gloss,G.Danet-Desnoyers,et al.2009.Chimeric receptors containing CD137signal transduction domains mediate enhanced survival of T cells and increased antileukemic ef?cacy in vivo.Mol.Ther.17:1453–1464.26.Grupp,S.A.,M.Kalos,D.Barrett,R.Aplenc,D.L.Porter,S.R.Rheingold,

D.T.Teachey,A.Chew,B.Hauck,J.F.Wright,et al.2013.Chimeric antigen receptor-modi?ed T cells for acute lymphoid leukemia.N.Engl.J.Med.368:1509–1518.

27.Maude,S.,N.Frey,P.Shaw,R.Aplenc, D.Barrett,N.Bunin, A.Chew,

V.Gonzalez,Z.Zheng,https://www.360docs.net/doc/d810907127.html,cey,et al.2014.Chimeric antigen receptor T cells for sustained remissions in leukemia.N.Engl.J.Med.371:1507–1517.

The Journal of Immunology 759

at Shandong Univ on March 30, 2016

https://www.360docs.net/doc/d810907127.html,/Downloaded from

28.Davila,M.L.,C.C.Kloss,G.Gunset,and M.Sadelain.2013.CD19CAR-targeted

T cells induce long-term remission and B cell aplasia in an immunocompetent mouse model of B cell acute lymphoblastic leukemia.PLoS ONE 8:e61338.

29.Kochenderfer,J.N.,Z.Yu,D.Frasheri,N.P.Restifo,and S.A.Rosenberg.2010.

Adoptive transfer of syngeneic T cells transduced with a chimeric antigen receptor that recognizes murine CD19can eradicate lymphoma and normal B cells.Blood 116:3875–3886.

30.Pegram,H.J.,J. C.Lee, E.G.Hayman,G.H.Imperato,T. F.Tedder,

M.Sadelain,and R.J.Brentjens.2012.Tumor-targeted T cells modi?ed to secrete IL-12eradicate systemic tumors without need for prior conditioning.Blood 119:4133–4141.

31.Rongvaux, A.,T.Willinger,J.Martinek,T.Strowig,S.V.Gearty,

L.L.Teichmann,Y.Saito,F.Marches,S.Halene,A.K.Palucka,et al.2014.Development and function of human innate immune cells in a humanized mouse model.Nat.Biotechnol.32:364–372.

32.van der Stegen,S.J.,D.M.Davies,S.Wilkie,J.Foster,J.K.Sosabowski,J.Burnet,

L.M.Whilding,R.M.Petrovic,S.Ghaem-Maghami,S.Mather,et al.2013.Preclinical in vivo modeling of cytokine release syndrome induced by ErbB-retargeted human T cells:identifying a window of therapeutic opportunity?J.Immunol.191:4589–4598.

33.Irving,B.A.,and A.Weiss.1991.The cytoplasmic domain of the T cell receptor

zeta chain is suf?cient to couple to receptor-associated signal transduction pathways.Cell 64:891–901.

34.Romeo,C.,and B.Seed.1991.Cellular immunity to HIV activated by CD4fused

to T cell or Fc receptor polypeptides.Cell 64:1037–1046.

35.Letourneur,F.,and R.D.Klausner.1991.T-cell and basophil activation through

the cytoplasmic tail of T-cell-receptor zeta family https://www.360docs.net/doc/d810907127.html,A 88:8905–8909.

36.Kuwana,Y.,Y.Asakura,N.Utsunomiya,M.Nakanishi,Y.Arata,S.Itoh,

F.Nagase,and Y.Kurosawa.1987.Expression of chimeric receptor composed of immunoglobulin-derived V regions and T-cell receptor-derived C https://www.360docs.net/doc/d810907127.html,mun.149:960–968.

37.Roberts,M.R.1997.Chimeric receptor molecules for delivery of co-stimulatory

signals.United States patent application 08/455,860.Publication https://www.360docs.net/doc/d810907127.html,5686281A.1997Nov 11.

38.Finney,H.M.,and https://www.360docs.net/doc/d810907127.html,wson.2003.Chimeric cytoplasmic signalling

molecules derived from CD137.United States patent application 10/399,364.Publication https://www.360docs.net/doc/d810907127.html,20040038886A1.2002Apr 25.

39.Carpenito,C.,https://www.360docs.net/doc/d810907127.html,one,R.Hassan,J.C.Simonet,https://www.360docs.net/doc/d810907127.html,khal,M.M.Suhoski,

A.Varela-Rohena,K.M.Haines,D.F.Heitjan,S.M.Albelda,et al.2009.Control of large,established tumor xenografts with genetically retargeted human T cells con-taining CD28and https://www.360docs.net/doc/d810907127.html,A 106:3360–3365.40.Davila,M.L.,I.Riviere,X.Wang,S.Bartido,J.Park,K.Curran,S.S.Chung,

J.Stefanski,O.Borquez-Ojeda,M.Olszewska,et al.2014.Ef?cacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia.Sci.Transl.Med.6:224ra25.

41.Long, A.H.,W.M.Haso,J. F.Shern,K.M.Wanhainen,M.Murgai,

M.Ingaramo,J.P.Smith,A.J.Walker,M.E.Kohler,V.R.Venkateshwara,et al.2015.4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors.Nat.Med.21:581–590.

42.Frigault,M.J.,J.Lee,M.C.Basil,C.Carpenito,S.Motohashi,J.Scholler,

O.U.Kawalekar,S.Guedan,S.E.McGettigan,A.D.Posey,Jr.,et al.2015.Identi?cation of chimeric antigen receptors that mediate constitutive or inducible proliferation of T cells.Cancer Immunol Res 3:356–367.

43.Porter,D.L.,B.L.Levine,M.Kalos,A.Bagg,and C.H.June.2011.Chimeric

antigen receptor-modi?ed T cells in chronic lymphoid leukemia.N.Engl.J.Med.365:725–733.

44.Kochenderfer,J.N.,W.H.Wilson,J.E.Janik,M.E.Dudley,M.Stetler-Stevenson,S.A.Feldman,I.Maric,M.Raffeld,D.A.Nathan,https://www.360docs.net/doc/d810907127.html,nier,et al.2010.Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19.Blood 116:4099–4102.

45.Maude,S.L.,D.Barrett,D.T.Teachey,and S.A.Grupp.2014.Managing cy-tokine release syndrome associated with novel T cell-engaging therapies.Cancer J.20:119–122.

46.Lee,D.W.,R.Gardner,D.L.Porter,C.U.Louis,N.Ahmed,M.Jensen,

S.A.Grupp,and C.L.Mackall.2014.Current concepts in the diagnosis and management of cytokine release syndrome.Blood 124:188–195.

47.Teachey,D.T.,S.R.Rheingold,S.L.Maude,G.Zugmaier,D.M.Barrett,

A.E.Seif,K.E.Nichols,E.K.Suppa,M.Kalos,R.A.Berg,et al.2013.Cy-tokine release syndrome after blinatumomab treatment related to abnormal macrophage activation and ameliorated with cytokine-directed therapy.Blood 121:5154–5157.

48.Kalos,M.,B.L.Levine,D.L.Porter,S.Katz,S.A.Grupp,A.Bagg,and

C.H.June.2011.T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia.Sci.Transl.Med.3:95ra73.

49.Morgan,R.A.,J.C.Yang,M.Kitano,M.E.Dudley,https://www.360docs.net/doc/d810907127.html,urencot,and

S.A.Rosenberg.2010.Case report of a serious adverse event following the ad-ministration of T cells transduced with a chimeric antigen receptor recognizing ERBB2.Mol.Ther.18:843–851.

50.Linette,G.P.,E.A.Stadtmauer,M.V.Maus,A.P.Rapoport,B.L.Levine,

L.Emery,L.Litzky,A.Bagg,B.M.Carreno,P.J.Cimino,et al.2013.Cardio-vascular toxicity and titin cross-reactivity of af?nity-enhanced T cells in myeloma and melanoma.Blood 122:863–871.

51.Cameron,B.J.,A.B.Gerry,J.Dukes,J.V.Harper,V.Kannan,F.C.Bianchi,

F.Grand,J.E.Brewer,M.Gupta,

G.Plesa,et al.2013.Identi?cation of a Titin-

derived HLA-A1–presented peptide as a cross-reactive target for engineered MAGE A3–directed T cells.Sci.Transl.Med.5:197ra103.

52.

Morgan,R.A.,N.Chinnasamy,D.Abate-Daga,A.Gros,P.F.Robbins,Z.Zheng,M.E.Dudley,S.A.Feldman,J.C.Yang,R.M.Sherry,et al.2013.Cancer re-gression and neurological toxicity following anti-MAGE-A3TCR gene therapy.J.Immunother.36:133–151.

53.

Lee,D.W.,J.N.Kochenderfer,M.Stetler-Stevenson,Y.K.Cui,C.Delbrook,S.A.Feldman,T.J.Fry,R.Orentas,M.Sabatino,N.N.Shah,et al.2015.T cells expressing CD19chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults:a phase 1dose-escalation https://www.360docs.net/doc/d810907127.html,ncet 385:517–528.54.

Rapoport,A.P.,E.A.Stadtmauer,N.Aqui,D.Vogl,A.Chew,H.B.Fang,S.Janofsky,K.Yager,E.Veloso,Z.Zheng,et al.2009.Rapid immune recovery and graft-versus-host disease-like engraftment syndrome following adoptive transfer of costimulated autologous T cells.Clin.Cancer Res.15:4499–4507.

55.

Grupp,S.A.,E.L.Prak,J.Boyer,K.R.McDonald,S.Shusterman,E.Thompson,C.Callahan,A.F.Jawad,B.L.Levine,C.H.June,and K.E.Sullivan.2012.Adoptive transfer of autologous T cells improves T-cell repertoire diversity and long-term B-cell function in pediatric patients with neuroblastoma.Clin.Cancer Res.18:6732–6741.

56.Marin,V.,E.Cribioli,B.Philip,S.Tettamanti,I.Pizzitola,A.Biondi,E.Biagi,and https://www.360docs.net/doc/d810907127.html,parison of different suicide-gene strategies for the safety improve-ment of genetically manipulated T cells.Hum.Gene.Ther.Methods 23:376–386.57.Mestas,J.,and C.C.Hughes.2004.Of mice and not men:differences between mouse and human immunology.J.Immunol.172:2731–2738.

58.

Straetemans,T.,M.Coccoris, C.Berrevoets, E.Treffers-Westerlaken,C.E.Scholten,D.Schipper,T.L.Ten Hagen,and R.Debets.2012.T-cell receptor gene therapy in human melanoma-bearing immune-de?cient mice:human but not mouse T cells recapitulate outcome of clinical studies.Hum.Gene Ther.23:187–201.

59.Abe,R.,P.Vandenberghe,N.Craighead,D.S.Smoot,K.P.Lee,and C.H.June.1995.Distinct signal transduction in mouse CD4+and CD8+splenic T cells after CD28receptor ligation.J.Immunol.154:985–997.

60.Maus,M.V.,B.Kovacs,W.W.Kwok,G.T.Nepom,K.Schlienger,J.L.Riley,D.Allman,T.H.Finkel,and C.H.June.2004.Extensive replicative capacity of human central memory T cells.J.Immunol.172:6675–6683.

61.Berger,C.,M.C.Jensen,https://www.360docs.net/doc/d810907127.html,nsdorp,M.Gough,C.Elliott,and S.R.Riddell.2008.Adoptive transfer of effector CD8+T cells derived from central memory cells establishes persistent T cell memory in primates.J.Clin.Invest.118:294–305.62.Kalos,M.,and C.H.June.2013.Adoptive T cell transfer for cancer immuno-therapy in the era of synthetic biology.Immunity 39:49–60.

63.

Thomas,A.K.,M.V.Maus,W.S.Shalaby,C.H.June,and J.L.Riley.2002.A cell-based arti?cial antigen-presenting cell coated with anti-CD3and CD28anti-bodies enables rapid expansion and long-term growth of CD4T lymphocytes.Clin.Immunol.105:259–272.

64.

Kaneko,S.,S.Mastaglio,A.Bondanza,M.Ponzoni,F.Sanvito,L.Aldrighetti,M.Radrizzani,https://www.360docs.net/doc/d810907127.html, Seta-Catamancio,E.Provasi,A.Mondino,et al.2009.IL-7and IL-15allow the generation of suicide gene-modi?ed alloreactive self-renewing central memory human T lymphocytes.Blood 113:1006–1015.

65.

Maus,M.V.,A.K.Thomas,D.G.Leonard,D.Allman,K.Addya,K.Schlienger,J.L.Riley,and C.H.June.2002.Ex vivo expansion of polyclonal and antigen-speci?c cytotoxic T lymphocytes by arti?cial APCs expressing ligands for the T-cell receptor,CD28and 4-1BB.Nat.Biotechnol.20:143–148.

66.

Paulos, C.M., C.Carpenito,G.Plesa,M.M.Suhoski, A.Varela-Rohena,T.N.Golovina,R.G.Carroll,J.L.Riley,and C.H.June.2010.The inducible costimulator (ICOS)is critical for the development of human T H 17cells.Sci.Transl.Med.2:55ra78.

67.Gattinoni,L.,E.Lugli,Y.Ji,Z.Pos,C.M.Paulos,M.F.Quigley,J.R.Almeida,E.Gostick,Z.Yu,C.Carpenito,et al.2011.A human memory T cell subset with stem cell-like properties.Nat.Med.17:1290–1297.

68.

Graef,P.,V.R.Buchholz,C.Stemberger,M.Flossdorf,L.Henkel,M.Schiemann,

I.Drexler,T.Ho

¨fer,S.R.Riddell,and D.H.Busch.2014.Serial transfer of single-cell-derived immunocompetence reveals stemness of CD8+central memory T cells.Immunity 41:116–126.

69.

Gattinoni,L.,X.S.Zhong, D. C.Palmer,Y.Ji, C.S.Hinrichs,Z.Yu,C.Wrzesinski,A.Boni,L.Cassard,L.M.Garvin,et al.2009.Wnt signaling arrests effector T cell differentiation and generates CD8+memory stem cells.Nat.Med.15:808–813.

70.

Moon,E.,C.Carpenito,J.Sun,L.Wang,V.Kapoor,J.Predina,D.Powell,Jr.,J.Riley,C.H.June,and S.M.Albelda.2011.2011.Expression of a functional CCR2receptor enhances tumor localization and tumor eradication by retargeted human T cells expressing a mesothelin-speci?c chimeric antibody receptor.Clin.Cancer Res.17:4719–4730.

71.Abastado,J.-P.2012.The next challenge in cancer immunotherapy:controlling T-cell traf?c to the tumor.Cancer Res.72:2159–2161.

72.Awwad,M.,and R.J.North.1990.Radiosensitive barrier to T-cell-mediated adoptive immunotherapy of established tumors.Cancer Res.50:2228–2233.

73.Ganss,R.,E.Ryschich,E.Klar,B.Arnold,and G.J.Ha

¨https://www.360docs.net/doc/d810907127.html,-bination of T-cell therapy and trigger of in?ammation induces remodeling of the vasculature and tumor eradication.Cancer Res.62:1462–1470.

74.

Pinthus,J.H.,T.Waks,V.Malina,K.Kaufman-Francis, A.Harmelin,I.Aizenberg,H.Kanety,J.Ramon,and Z.Eshhar.2004.Adoptive immunotherapy of prostate cancer bone lesions using redirected effector lymphocytes.J.Clin.Invest.114:1774–1781.

75.

Ward-Kavanagh,L.K.,J.Zhu,T.K.Cooper,and T.D.Schell.2014.Whole-body irradiation increases the magnitude and persistence of adoptively transferred T cells associated with tumor regression in a mouse model of prostate cancer.Cancer Immunol Res 2:777–788.

760TRANSLATING IMMUNOLOGY:CAR-AND TCR-ENGINEERED T CELLS

at Shandong Univ on March 30, 2016

https://www.360docs.net/doc/d810907127.html,/Downloaded from

76.Qiao,J.,T.Kottke, C.Willmon, F.Galivo,P.Wongthida,R.M.Diaz,

J.Thompson,P.Ryno,G.N.Barber,J.Chester,et al.2008.Purging metastases in lymphoid organs using a combination of antigen-nonspeci?c adoptive T cell ther-apy,oncolytic virotherapy and immunotherapy.Nat.Med.14:37–44.

77.Duval,L.,H.Schmidt,K.Kaltoft,K.Fode,J.J.Jensen,S.M.Sorensen,

M.I.Nishimura,and H.von der Maase.2006.Adoptive transfer of allogeneic cytotoxic T lymphocytes equipped with a HLA-A2restricted MART-1T-cell re-ceptor:a phase I trial in metastatic melanoma.Clin.Cancer Res.12:1229–1236.78.Cieri,N.,B.Camisa,F.Cocchiarella,M.Forcato,G.Oliveira,E.Provasi,A.Bondanza,

C.Bordignon,J.Peccatori,F.Ciceri,et al.2013.IL-7and IL-15instruct the generation of human memory stem T cells from naive precursors.Blood 121:573–584.

79.Guedan,S.,X.Chen, A.Madar, C.Carpenito,S. E.McGettigan,

M.J.Frigault,J.Lee,A.D.Posey,Jr.,J.Scholler,N.Scholler,et al.2014.ICOS-based chimeric antigen receptors program bipolar T H 17/T H 1cells.Blood 124:1070–1080.

80.Hinrichs, C.S., A.Kaiser, C.M.Paulos,L.Cassard,L.Sanchez-Perez,

B.Heemskerk,

C.Wrzesinski,Z.A.Borman,P.Muranski,and N.P.Restifo.2009.Type 17CD8+T cells display enhanced antitumor immunity.Blood 114:596–https://www.360docs.net/doc/d810907127.html,mers,C.H.,S.Sleijfer,A.G.Vulto,W.H.Kruit,M.Kliffen,R.Debets,

J.W.Gratama,G.Stoter,and E.Oosterwijk.2006.Treatment of metastatic renal cell carcinoma with autologous T-lymphocytes genetically retargeted against car-bonic anhydrase IX:?rst clinical experience.J.Clin.Oncol.24:e20–e22.

82.Zhao,Y.,E.Moon,C.Carpenito,C.M.Paulos,X.Liu,A.L.Brennan,A.Chew,

R.G.Carroll,J.Scholler,B.L.Levine,et al.2010.Multiple injections of elec-

troporated autologous T cells expressing a chimeric antigen receptor mediate re-gression of human disseminated tumor.Cancer Res.70:9053–9061.

83.

Beatty,G.L.,A.R.Haas,M.V.Maus,D.A.Torigian,M.C.Soulen,G.Plesa,A.Chew,Y.Zhao,B.L.Levine,S.M.Albelda,et al.2014.Mesothelin-speci?c chimeric antigen receptor mRNA-engineered T cells induce anti-tumor activity in solid malignancies.Cancer Immunol Res 2:112–120.

84.Di Stasi,A.,S.K.Tey,G.Dotti,Y.Fujita,A.Kennedy-Nasser,C.Martinez,K.Straathof,E.Liu,A.G.Durett,B.Grilley,et al.2011.Inducible apoptosis as a safety switch for adoptive cell therapy.N.Engl.J.Med.365:1673–1683.

85.

Wiek,C.,E.M.Schmidt,K.Roellecke,M.Freund,M.Nakano,E.J.Kelly,W.Kaisers,V.Yarov-Yarovoy,C.M.Kramm,A.E.Rettie,and H.Hanenberg.2015.Identi?cation of amino acid determinants in CYP4B1for optimal catalytic processing of 4-ipomeanol.Biochem.J.465:103–114.

86.

Tebas,P.,D.Stein,W.W.Tang,I.Frank,S.Q.Wang,G.Lee,S.K.Spratt,R.T.Surosky,M.A.Giedlin,G.Nichol,et al.2014.Gene editing of CCR5in autologous CD4T cells of persons infected with HIV.N.Engl.J.Med.370:901–910.

87.

Torikai,H., A.Reik, F.Soldner, E.H.Warren, C.Yuen,Y.Zhou,D.L.Crossland,H.Huls,N.Littman,Z.Zhang,et al.2013.Toward eliminating HLA class I expression to generate universal cells from allogeneic donors.Blood 122:1341–1349.

88.

Prosser,M.E.,C.E.Brown,A.F.Shami,S.J.Forman,and M.C.Jensen.2012.Tumor PD-L1co-stimulates primary human CD8+cytotoxic T cells modi?ed to express a PD1:CD28chimeric receptor.Mol.Immunol.51:263–272.

The Journal of Immunology

761

at Shandong Univ on March 30, 2016

https://www.360docs.net/doc/d810907127.html,/Downloaded from