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416 Part V: Therapeutic Principles Chapter 26: Immune Cell Therapy 417

intensive supportive care, and treatment with glucocorticoids and/or (Erbitux) has been developed, but its efficacy for ablating transferred T
anti IL-6 receptor antibodies. CAR-T cells often do not persist long cells in patients has not been established.
term, although prolonged B-cell aplasia has been observed in a subset
of patients.
The finding that durable responses can be achieved in some FUTURE DIRECTIONS IN T-CELL
patients with advanced B-cell malignancies illustrates the potency of THERAPY
CAR-T cells, and suggests that future work to define optimal design of
the CD19 CAR constructs and to identify the optimal subset(s) of T The field of adoptive T-cell therapy is now emerging as a viable and
cells to modify may further improve outcomes, particularly in CLL and effective therapeutic approach for treating human infections and cancer.
lymphoma where response rates and durability are lower. The demon- Advances in the understanding of cell intrinsic properties of T-cell sub-
stration of the superior engraftment properties of effector T (T ) cells sets, discovery of target antigens that distinguish tumor cells from nor-
E
derived from T CM would suggest that selection or enrichment of T mal cells, and improvements in the methodology for introducing genes
CM
prior to gene insertion may provide a superior T-cell product for adop- into T cells have combined to make it feasible to treat patients with cer-
tive therapy. 48,194 This hypothesis is being examined prospectively in tain malignancies using highly effective T-cell products. Several chal-
clinical trials of CAR–T-cell therapy. Moreover, integrating T-cell ther- lenges remain. For most common human tumors, target antigens have
apy earlier after diagnosis or after autologous HSCT, in which marked not yet been defined, and tumor heterogeneity and other mechanisms
tumor cytoreduction can be achieved by intensive conditioning, may that tumors use to evade T-cell recognition represent barriers to effec-
further improve outcome and reduce the toxicity resulting from CAR- tive therapy. Thus, additional research to identify and validate a larger
mediated tumor lysis. number of target molecules for TCR- and CAR-recognition is essential
CAR-modified T cells also may have applications in the treatment to broaden therapeutic applications, and improve efficacy. Combination
of solid tumors. Candidate surface molecules on solid tumors that are therapies with T cells and checkpoint inhibitors are promising for over-
187
being actively pursued as targets include GD2, mesothelin, L1-cell coming local and systemic evasion mechanisms that limit antitumor
186
adhesion molecule (L1CAM), ROR1, 170,171 prostate stem cell antigen, immunity. Finally, it would be ideal if expression of the tumor targeting
85
195
197
196
folate receptor, and the fibroblast activation protein. Significant receptors or the survival of transferred T cells were under regulatory
antitumor activity without toxicity has been reported in patients with control by small molecules that could be administered to the patient to
neuroblastoma treated with T cells modified with a first-generation reduce toxicity.
GD2 CAR. The persistence of the transferred cells was relatively short
186
in that study, however, perhaps owing to the lack of costimulation in
the CAR. GD2 is expressed on normal peripheral nerves, and on-target REFERENCES
toxicity from a sustained T-cell response will need to be monitored if 1. Klenerman P, Hill A: T cells and viral persistence: Lessons from diverse infections. Nat
more potent CARs are being examined. Suitable animal models for Immunol 6:873, 2005.
preclinical toxicity studies are urgently needed and are being devel- 2. Tomblyn M, Chiller T, Einsele H, et al: Guidelines for preventing infectious complica-
oped. 197–199 It will also be important to address the multiple evasion tions among hematopoietic cell transplantation recipients: A global perspective. Biol
Blood Marrow Transplant 15:1143, 2009.
96
mechanisms that tumors employ to avoid immune elimination. For 3. Pollack M, Heugel J, Xie H, et al: An international comparison of current strategies to
example, the programmed death-1 (PD-1) receptor is a negative regula- prevent herpesvirus and fungal infections in hematopoietic cell transplant recipients.
Biol Blood Marrow Transplant 17:664, 2011.
tor of T mechanisms that limits immune responses against cancer, and 4. Wingard JR, Hsu J, Hiemenz JW: Hematopoietic stem cell transplantation: An overview
E
the combination of checkpoint blockade and T-cell therapy is of future of infection risks and epidemiology. Hematol Oncol Clin North Am 25:101, 2011.
interest. 200–202 5. Hsu JW, Wingard JR: Advances in the management of viral infections. Cancer Treat Res
161:157, 2014.
6. Riddell SR, Greenberg PD: T-cell therapy of cytomegalovirus and human immunodefi-
ciency virus infection. J Antimicrob Chemother 45 (Suppl T3):35, 2000.
Suicide Genes for Conditional Ablation 7. Leen AM, Heslop HE, Brenner MK: Antiviral T-cell therapy. Immunol Rev 258:12, 2014.
The results of clinical trials of T-cell therapy have revealed toxicity to 8. Boeckh M, Geballe AP: Cytomegalovirus: Pathogen, paradigm, and puzzle. J Clin Invest
normal tissues in some patients. The introduction of a suicide gene into 121:1673, 2011.
the T cells that could be activated if toxicity occurred has long been 9. Powers C, DeFilippis V, Malouli D, et al: Cytomegalovirus immune evasion. Curr Top
Microbiol Immunol 325:333, 2008.
the subject of research. The HSV-thymidine kinase (HSV-TK) gene 10. Sylwester AW, Mitchell BL, Edgar JB, et al: Broadly targeted human cytomegalovirus-
has been used in gene therapy trials in the clinic and was effective in specific CD4+ and CD8+ T cells dominate the memory compartments of exposed sub-
jects. J Exp Med 202:673, 2005.
203
reversing GVHD after DLI. However, the viral thymidine kinase is 11. Manley TJ, Luy L, Jones T, et al: Immune evasion proteins of human cytomegalovirus
immunogenic and can result in premature elimination of transferred T do not prevent a diverse CD8+ cytotoxic T cell response in natural infection. Blood
cells that do not cause toxicity. Novel suicide genes based on induc- 104:1075, 2004.
204
ing conditional cell death through activation of CD95 (Fas) or caspases 12. Li C-R, Greenberg PD, Gilbert MJ, et al: Recovery of HLA-restricted cytomegalovirus
using a chemical dimerizer such as AP1903 to activate an engineered (CMV)-specific T-cell responses after allogeneic bone marrow transplant: Correlation
with CMV disease and effect of ganciclovir prophylaxis. Blood 83:1971, 1994.
chimeric human CD95 or caspase transgene product may circumvent 13. Boeckh M, Nichols WG, Papanicolaou G, et al: Cytomegalovirus in hematopoietic stem
the problem of immunogenicity. 205–207 Recently, 10 patients undergo- cell transplant recipients: Current status, known challenges, and future strategies. Biol
Blood Marrow Transplant 9:543, 2003.
ing haploidentical HSCT for relapsed acute leukemia were treated with 14. McGoldrick SMB: Cytomegalovirus-specific T cells are primed early after cord blood
donor T cells modified to express an inducible caspase9 gene (iCasp9). transplant but fail to control virus in vivo. Blood 121:2796, 2013.
The iCasp9 T cells engrafted and conferred protection against infectious 15. Sellar RS, Peggs KS: Therapeutic strategies for cytomegalovirus infection in haemato-
diseases. A subset of the patients developed GVHD. A single dose of the poietic transplant recipients: A focused update. Expert Opin Biol Ther 14:1121, 2014.
dimerizing drug, given to those patients who developed GVHD ablated 16. Reusser P, Einsele H, Lee J, et al: Randomized multicenter trial of foscarnet versus gan-
ciclovir for preemptive therapy of cytomegalovirus infection after allogeneic stem cell
more than 90 percent of the iCasp9-modified T cells rapidly and elim- transplantation. Blood 99:1159, 2002.
inated the GVHD without recurrence or adverse events. 208,209 A trun- 17. Marty FM, Winston DJ, Rowley SD, et al: CMX001 to prevent cytomegalovirus disease
in hematopoietic-cell transplantation. N Engl J Med 369:1227, 2013.
cated epidermal growth factor receptor (EGFR) marker/suicide gene 18. Chemaly RF, Ullmann AJ, Stoelben S, et al: Letermovir for cytomegalovirus prophylaxis
that could be targeted in vivo using a clinical grade anti-EGFR antibody in hematopoietic-cell transplantation. N Engl J Med 370:1781, 2014.

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