RORing T cells target CLL and MCL

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BlankBlood, 25 November 2010, Vol. 116, No. 22, pp. 4387-4388.

RORing T cells target CLL and MCL

Michel Sadelain

MEMORIAL SLOAN-KETTERING CANCER CENTER

Genetically targeted T lymphocytes are emerging as powerful antitumor agents.

Their rapid generation, made possible by robust and clinically applicable gene

transfer technologies, provides a novel means to circumvent immune tolerance and

generate tumor-reactive T cells on demand. Thus, patient peripheral blood T

cells can be readily redirected toward any chosen antigen, including tumor

antigens which are for the most part " self " antigens, and infused to promptly

raise the number of tumor-reactive T cells without requiring active immunization

and without the risk of deleterious alloreactivity (as may be the case after

donor leukocyte infusion or non-T cell–depleted bone marrow transplantation).

The genetic engineering of T cells, mediated by several vector systems (among

which (gamma)-retroviral vectors are currently preponderant), aims not only to

redirect the antigen specificity of T cells but also to generate T cells that

are endowed with enhanced signaling and other antitumoral properties to sustain

their survival and function within the tumor microenvironment.1,2 What T-cell

type (naive T cells, memory T cells, virus-specific T cells, T-cell precursors)

to engineer " for best results " remains a hotly debated topic.

Antigen specificity is imparted by the genetic transfer of a single antigen

receptor, consisting of either physiologic, HLA-restricted T-cell receptors

(TCRs)3 or artificial, non-HLA-restricted receptors, which vary in the molecular

composition and are broadly referred to as chimeric antigen receptor (CARs).4

Most CARs use an antibody-derived antigen-binding motif to recognize antigen,

and comprise activating and costimulatory signaling domains in their cytoplasmic

portion. CARs are thus targeted to cell-surface antigens and do not have to be

matched to the patient's HLA.

In the hematologic malignancies, CD19, which is relevant to chronic and acute

leukemias as well as non-Hodgkin lymphomas, has emerged as a pivotal target

antigen.5,6 It is the focus of more than a dozen active protocols in the United

States, all of which are based on the infusion of CD19-targeted T cells. Over 15

centers are planning trials based on this approach in the United States, Europe,

and Japan. At a recent meeting of the BMT CTN Network held in May 2010, it was

determined that 19 patients had already been treated with CD19-targeted T cells

in the United States. CD19 is normally expressed in the B-cell lineage from the

pro-B-cell stage on albeit not in plasma cells. Importantly, it is not found in

hematopoietic stem cells and in other hematopoietic lineages. The targeting of

CD19 is thus expected to induce B-cell aplasia, which has been verified in

animal models. The duration and consequences of this induced B-cell deficit are

yet to be fully investigated, but there is ample precedent for the successful

clinical management of similar conditions after bone marrow transplantation or

monoclonal antibody therapy. The broad relevance of CD19 to the majority of

leukemias and lymphomas notwithstanding, the availability of a highly

tumor-specific target antigen would avert the risk of a sustained B-cell

deficit.

In this issue of Blood, Hudecek et al establish ROR1 as a novel target for

CAR-mediated T-cell therapy.7 ROR1 is a cell-surface antigen receptor with an

extra cellular domain that contains Ig-like, Frizzled and Kringle domains, which

may act in Wnt signaling and promote tumor cell survival.8,9 It is expressed

during fetal development and not known to be expressed postnatally elsewhere

than in early maturing B cells, the pancreas, and adipose tissue.9

Significantly, it is expressed at a high level in chronic lymphocytic leukemia

(B-CLL), a subset of acute lymphoblastic leukemia (B-ALL), and, as shown by

Hudecek et al, in mantle cell lymphoma (MCL). In their study, Hudecek and

colleagues describe a novel ROR1-specific CAR and demonstrate its ability to

redirect patient T cells against CLL and MCL tumor cells, resulting in efficient

in vitro cytotoxicity and other key functional T-cell responses including

cytokine secretion and proliferation. While these studies stop short of

demonstrating T-cell efficacy in mice bearing systemic leukemia or lymphoma—and

a much-anticipated comparison to CD19 targeting—this report conclusively brings

ROR1 to the fore as an attractive target for immunotherapeutic strategies in

selected leukemias and lymphomas.

As the potency of genetically enhanced T lymphocytes gains strength, so does the

concern over toxicity, including on-target effects (whereby T cells attack

tissues that normally express the targeted antigen). Several reports underscore

the ability of genetically targeted T cells to react against normal tissues, for

example, carbonic anhydrase IX in biliary epithelium10 and MART-1 in the inner

ear,11 eye, and in patients with renal cancer or melanoma who were given T cells

targeted against these antigens. These undesirable effects may, however, be

manageable and do not constitute grounds for not investigating differentiation

antigens such as CD19 (which is highly restricted to the B-cell lineage) or an

oncofetal antigen-like receptor such as ROR1. The consequences of low-level ROR1

expression in adipocytes and possibly some pancreatic cells will have to be

closely investigated.

Footnotes

Conflict-of-interest disclosure: The author declares no competing financial

interests.

REFERENCES

1.. Sadelain M, Riviere I, Brentjens R. Targeting tumours with genetically

enhanced T lymphocytes. Nat Rev Cancer. 2003;3(1):35–45

2.. Ho WY, Blattman JN, Dossett ML, Yee C, Greenberg PD. Adoptive

immunotherapy: engineering T cell responses as biologic weapons for tumor mass

destruction. Cancer Cell. 2003;3(5):431–437.[CrossRef

3.. Bendle GM, Haanen JB, Schumacher TN. Preclinical development of T cell

receptor gene therapy. Curr Opin Immunol. 2009;21(2):209–214.

4.. Sadelain M, Brentjens R, Riviere I. The promise and potential pitfalls of

chimeric antigen receptors. Curr Opin Immunol. 2009;21(2):215–223

5.. Brentjens RJ, Latouche JB, Santos E, et al. Eradication of systemic B-cell

tumors by genetically targeted human T lymphocytes co-stimulated by CD80 and

interleukin-15. Nat Med. 2003;9(3):279–286.

6.. LJ, Topp MS, Serrano LM, et al. T-cell clones can be rendered

specific for CD19: toward the selective augmentation of the

graft-versus-B-lineage leukemia effect. Blood. 2003;101(4):1637–1644

7.. Hudecek M, Schmitt TM, Baskar S, et al. The B-cell tumor-associated

antigen ROR1 can be targeted with T cells modified to express a ROR1-specific

chimeric antigen receptor. Blood. 2010;116(22):4532–4541

8.. Fukuda T, Chen L, Endo T, et al. Antisera induced by infusions of

autologous Ad-CD154-leukemia B cells identify ROR1 as an oncofetal antigen and

receptor for Wnt5a. Proc Natl Acad Sci U S A. 2008;105(8):3047–3052.

9.. Forrester WC. The Ror receptor tyrosine kinase family. Cell Mol Life Sci.

2002;59(1):83–96.

10.. Lamers CH, Sleijfer S, Vulto AG, et al. Treatment of metastatic renal

cell carcinoma with autologous T-lymphocytes genetically retargeted against

carbonic anhydrase IX: first clinical experience. J Clin Oncol.

2006;24(13):e20–e22

11.. LA, RA, Dudley ME, et al. Gene therapy with human and

mouse T-cell receptors mediates cancer regression and targets normal tissues

expressing cognate antigen. Blood. 2009;114(3):535–546.[