Preclinical in vivo modeling of cytokine release syndrome induced by ErbB-retargeted human T cells: identifying a window of therapeutic opportunity?
The ErbB network is dysregulated in many solid tumors. To exploit this, we have developed a chimeric Ag receptor (CAR) named T1E28z that targets several pathogenetically relevant ErbB dimers. T1E28z is coexpressed with a chimeric cytokine receptor named 4αβ (combination termed T4), enabling the selective expansion of engineered T cells using IL-4. Human T4(+) T cells exhibit antitumor activity against several ErbB(+) cancer types. However, ErbB receptors are also expressed in several healthy tissues, raising concerns about toxic potential. In this study, we have evaluated safety of T4 immunotherapy in vivo using a SCID beige mouse model. We show that the human T1E28z CAR efficiently recognizes mouse ErbB(+) cells, rendering this species suitable to evaluate preclinical toxicity. Administration of T4(+) T cells using the i.v. or intratumoral routes achieves partial tumor regression without clinical or histopathologic toxicity. In contrast, when delivered i.p., tumor reduction is accompanied by dose-dependent side effects. Toxicity mediated by T4(+) T cells results from target recognition in both tumor and healthy tissues, leading to release of both human (IL-2/IFN-γ) and murine (IL-6) cytokines. In extreme cases, outcome is lethal. Both toxicity and IL-6 release can be ameliorated by prior macrophage depletion, consistent with clinical data that implicate IL-6 in this pathogenic event. These data demonstrate that CAR-induced cytokine release syndrome can be modeled in mice that express target Ag in an appropriate distribution. Furthermore, our findings argue that ErbB-retargeted T cells can achieve therapeutic benefit in the absence of unacceptable toxicity, providing that route of administration and dose are carefully optimized.
Department of Research Oncology, King's Health Partners Integrated Cancer Centre, King's College London, London SE1 9RT, United Kingdom;
Sjoukje J C
SJ
van der Stegen
David M
DM
Davies
Scott
S
Wilkie
Julie
J
Foster
Jane K
JK
Sosabowski
Jerome
J
Burnet
Lynsey M
LM
Whilding
Roseanna M
RM
Petrovic
Sadaf
S
Ghaem-Maghami
Stephen
S
Mather
Jean-Pierre
JP
Jeannon
Ana C
AC
Parente-Pereira
John
J
Maher
D000818:Animals; D002460:Cell Line; D006801:Humans; D016219:Immunotherapy, Adoptive; D007371:Interferon-gamma / Q000096:biosynthesis / Q000378:metabolism; D007376:Interleukin-2 / Q000096:biosynthesis / Q000378:metabolism; D015847:Interleukin-4; D015850:Interleukin-6 / Q000096:biosynthesis / Q000378:metabolism; D008264:Macrophages; D051379:Mice; D016513:Mice, SCID; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy; D018739:Oncogene Proteins v-erbB / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism*
D007376:Interleukin-2; D015850:Interleukin-6; D018739:Oncogene Proteins v-erbB; D011993:Recombinant Fusion Proteins; D015847:Interleukin-4; D007371:Interferon-gamma