Define “humanized”: two mouse models helping produce cancer immunotherapies

Official numbers say that we are winning our war on cancer: mortality rates corrected for aging have fallen by 17% from 1990 to 2016 and are still declining. Some say cancer prevalence is decreasing because of earlier detection, others because of improved treatment.¹ What is certain is that recent decades have seen a significant boost of immunotherapeutic approaches that have dramatically contributed to improved survival rates for several cancer types. For example, patients suffering from some solid cancers and hematological malignancies, whose outcomes were once invariably terminal, can now be treated with immunotherapy drugs (e.g., ipilimumab, nivolumab) or CAR T-cell therapy, and experience durable remissions.^2,3

These important advances are mainly due to the generation of sophisticated preclinical models that translate better to the human situation, and therefore help scientists to improve the design of clinical trials in cancer immunotherapy. Among those are human immune system (HIS) and humanized immune checkpoint (ICP) mice.^4-6

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Although both models are humanized, each is done differently. HIS are immunocompromised mice reconstituted with human cellular and molecular components to develop a human immune system: when engrafted with tumors of human origins, they represent invaluable tools to study and predict therapy-induced immune responses in vivo.^6-8

Humanized ICP models are genetically modified by Knockin at specific loci, resulting in the replacement of the murine protein with the human counterpart. As such, they preserve the target-ligand interaction as well as the molecular and cellular communication between stromal and cancer cells. For this reason, especially when injected with humanized ICP tumor cell lines originating from the very same genetic background (i.e., syngeneic models), humanized ICP mice provide important insights into the process of metastasis, and into the efficacy of mono and combination therapies targeting human ICPs.⁹

HIS and ICP mice are therefore complementary models as, when used together, they allow not only to assess the efficacy and safety of immunotherapies, but also to determine the immune response elicited by the treatment.

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References:

1. Max Roser, Ritchie H. Cancer Survival Rates. Accessed September 24, 2020. https://ourworldindata.org/cancer
2. Barbari C, Fontaine T, Parajuli P, et al. Immunotherapies and Combination Strategies for Immuno-Oncology. IJMS. 2020;21(14):5009. doi:10.3390/ijms21145009
3. Holstein SA, Lunning MA. CAR T-Cell Therapy in Hematologic Malignancies: A Voyage in Progress. Clin Pharmacol Ther. 2020;107(1):112-122. doi:10.1002/cpt.1674
4. Bedognetti D, Ceccarelli M, Galluzzi L, et al. Toward a comprehensive view of cancer immune responsiveness: a synopsis from the SITC workshop. J Immunother Cancer.2019;7(1):131. doi:10.1186/s40425-019-0602-4
5. Yip H, Haupt C, Maresh G, Zhang X, Li L. Humanized mice for immune checkpoint blockade in human solid tumors. Am J Clin Exp Urol. 2019;7(5):313-320.
6. Simpson JA, Brown ME. Making HIS mice more human-like. J Leukoc Biol. 2020;107(1):9-10. doi:10.1002/JLB.5CE1019-262R
7. Lopez-Lastra S, Masse-Ranson G, Fiquet O, et al. A functional DC cross talk promotes human ILC homeostasis in humanized mice. Blood Advances. 2017;1(10):601-614. doi:10.1182/bloodadvances.2017004358
8. Legrand N, Huntington ND, Nagasawa M, et al. Functional CD47/signal regulatory protein alpha (SIRPα) interaction is required for optimal human T- and natural killer- (NK) cell homeostasis in vivo. Proc Natl Acad Sci USA. 2011;108(32):13224-13229. doi:10.1073/pnas.1101398108
9. Plava J, Cihova M, Burikova M, Matuskova M, Kucerova L, Miklikova S. Recent advances in understanding tumor stroma-mediated chemoresistance in breast cancer. Mol Cancer. 2019;18(1):67. doi:10.1186/s12943-019-0960-z