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Chapter 1
of Pennsylvania, Pennsylvania, United States of America) reported complete remissions in
2 out of 3 chronic lymphocytic leukemia patients treated with anti-CD19 CAR:CD137-CD3z
T cells (41, 42). In two separate studies, patients with B cell malignancies were treated with
anti-CD19 CAR:CD28-CD3z T cells resulting in 1 complete and 5 partial responses out of 8
patients treated in the first study (43) and 4 out of 5 partial responses in patients treated with
cyclophosphamide and CAR T cells (44).
1.2 ChallEngES Of TCR gEnE ThERaPy
The two main challenges of TCR gene therapy are 1) improvement of the anti-tumor response
and 2) prevention/limitation of toxicity. In Table 3, I have further defined these challenges and
indicated potential therapeutic strategies to address these challenges. Chapter 2 provides a
detailed overview of the challenges and solutions. In short:
Challenge 1: Improve anti-tumor responses
Compromised anti-tumor responses are either related to the infused TCR T cells or the tumor.
T-cell related factors include limited avidity, in vivo persistence, expansion, and homing and
effector functions of T cells. Tumor-related factors include target antigen, such as its accessibility
and level of expression, and tumor-induced immune suppression.
Challenge 2: Prevent/limit toxicities
Toxicities of TCR gene therapy can be divided into on-target and off-target toxicities. Ontarget
toxicity represents toxicity related to the T cell target antigen, which can occur in case
the antigen is expressed, even at low levels, on healthy non-tumor tissue. This type of toxicity
can be prevented by choosing a target antigen of which the expression is restricted to tumor
tissue, see paragraph 1.4. Off-target toxicity is a direct consequence of TCR-mispairing, i.e. the
incorrect pairing of the introduced and endogenous TCRab chains (28, 47). Consequences of
TCR-mispairing are diluted expression of the introduced TCR but more problematically the
occurrence of unknown TCR specificities that potentially result in auto-reactivity. Preclinical
findings in a mouse model of TCR gene therapy (48) and in vitro systems in human T cells (49)
stress the use of strategies to prevent the occurrence of TCR-mispairing. Strategies to prevent
TCR-mispairing are described in chapter 2 and in (28).
1.3 MOuSE TuMOR MODElS fOR TCR gEnE ThERaPy
The development of cancer is the result of a cascade of mutations that makes the disease
process complex and difficult to model. Animal models used to translate experimental find-
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