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TCR gene therapy: lessons from (pre)clinical studies
major challenges, namely: 1) on-target toxicity; 2) compromised anti-tumour T cell responses;
3) compromised T cell persistence; and 4) immunogenicity of receptor transgenes, which will
all be discussed, together with potential solutions, in more detail in the following sections.
2.2 fIRST ChallEngE: On-TaRgET TOXICITy
Several ACT studies using expanded T cell populations in mice (18-21) and humans (3) as
well as two recent receptor gene therapy studies (13, 14) demonstrated the occurrence of
toxicities of healthy tissues expressing cognate antigen. For example, Lamers and colleagues
treated renal cell carcinoma (RCC) patients with T cells engineered with an antibody-based
receptor directed towards Carbonic Anhydrase IX (CAIX) and observed severe liver toxicity
that was most probably due to expression of the target antigen on the large bile ducts of
liver. In the study by Johnson and colleagues, healthy tissues in skin, ears and eyes were
targeted by T cells engineered with a TCRab directed against MART-I/A2. Although such toxicities
can often be suppressed and even reversed, these studies strongly suggest that T cell
therapy should be directed against safer target antigens of which the expression is restricted
to malignant tissues. For a comprehensive review of possible suitable and non-suitable target
antigens for ACT studies we refer to a recent review (22).
Antigens that show tumour-specific expression are those that belong to either mutated
or shared antigens (23). Mutated or unique antigens, such as CDK-4/m, provide safe T cell
targets yet the vast majority of these antigens is expressed in individual tumours making
their clinical utility at present difficult (24). In contrast, shared antigens, such as ‘Cancer testis
Antigens’ (CTA), are expressed in many tumours but silenced in normal cells except male
germline cells (being devoid of MHC molecules) and thymic medullary epithelial cells (expression
detected at the mRNA level) (25, 26). These qualities put CTA forward as candidate
tumour antigens for T cell therapy. In vitro studies have already shown that gene transfer
of TCRab directed against MAGE-A1/A1, NY-ESO-1/A2 as well as NY-ESO-1/DP4 can result
in effective T cell responses against tumour cells expressing cancer testis antigens (27-29).
Of the group of cancer-germline genes, in particular the MAGE genes constitute attractive
candidates given not only tumour-specific expression but also their role in tumour biology,
expression in multiple tumours and potential to constitute effective T cell targets. There are
four families of MAGE genes located on chromosome X: MAGE-A (12 genes), B (6 genes), C (4
genes) and D (2 genes). Up to now, over 50 combinations of MAGE peptides and HLA class I or
class II molecules have been identified, recognized by CD8 or CD4 T cells, respectively. Several
MAGE proteins have recently been recognized for their active contribution to the development
of malignancies. MAGE-A, B and C antigens suppress p53-dependent apoptosis (30),
whereas MAGE-A3 antigen mediates fibronectin-controlled progression and metastasis (31),
and is expressed by melanoma stem cells (32). Furthermore, MAGE antigens are expressed by
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