A rational mouse model to detect on-target, off-tumor CAR T cell toxicity

Castellarin, Mauro; Sands, Caroline; Da, Tong; Scholler, John; Graham, Kathleen; Buza, Elizabeth L.; Fraietta, Joseph A.; Zhao, Yangbing; June, Carl H.

doi:10.1172/jci.insight.136012

Cited by 67 publications

(64 citation statements)

References 51 publications

(56 reference statements)

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“…To improve its efficacy-safety profile, this therapy was affinitytuned to detect tumor cells with a high density of surface antigens, while sparing normal cells with lower antigen expression (39). A mouse model expressing human Her2 was used to confirm the safer profile of the low affinity CART (40). Using the Lung-and Intestine-Chips, we similarly identified a reduced risk of healthy tissue targeting with a low affinity TCB for both the FOLR1 and CEA targets.…”

Section: Discussionmentioning

confidence: 99%

Human immunocompetent Organ-on-Chip platforms allow safety profiling of tumor-targeted T-cell bispecific antibodies

Kerns

Belgur

Petropolis

et al. 2021

eLife

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Traditional drug safety assessment often fails to predict complications in humans, especially when the drug targets the immune system. Here, we show the unprecedented capability of two human Organs-on-Chips to evaluate the safety profile of T-cell bispecific antibodies (TCBs) targeting tumor antigens. Although promising for cancer immunotherapy, TCBs are associated with an on-target, off-tumor risk due to low levels of expression of tumor antigens in healthy tissues. We leveraged in vivo target expression and toxicity data of TCBs targeting folate receptor 1 (FOLR1) or carcinoembryonic antigen (CEA) to design and validate human immunocompetent Organs-on-Chips safety platforms. We discovered that the Lung-Chip and Intestine-Chip could reproduce and predict target-dependent TCB safety liabilities, based on sensitivity to key determinants thereof, such as target expression and antibody affinity. These novel tools broaden the research options available for mechanistic understandings of engineered therapeutic antibodies and assessing safety in tissues susceptible to adverse events.

show abstract

Section: Discussionmentioning

confidence: 99%

Human immunocompetent Organ-on-Chip platforms allow safety profiling of tumor-targeted T-cell bispecific antibodies

Kerns

Belgur

Petropolis

et al. 2021

eLife

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show abstract

“…To improve its efficacy-safety profile, this therapy was affinity-tuned to detect tumor cells with a high density of surface antigens, while sparing normal cells with lower antigen expression(39). A mouse model expressing human Her2 was used to confirm the safer profile of the low affinity CART(40). Using the Lung- and Intestine-Chips, we similarly identified a reduced risk of healthy tissue targeting with a low affinity TCB for both the FOLR1 and CEA targets.…”

Section: Discussionmentioning

confidence: 99%

Human immunocompetent Organ-on-Chip platforms allow safety profiling of tumor-targeted T-cell bispecific antibodies

Kerns

Belgur

Petropolis

et al. 2021

Preprint

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Traditional drug safety assessment often fails to predict complications in humans, especially when the drug targets the immune system. Here, we show the unprecedented capability of two Organs-on-Chips to evaluate the safety profile of T-cell bispecific antibodies (TCBs) targeting tumor antigens. Although promising for cancer immunotherapy, TCBs are associated with an on-target, off-tumor risk due to low levels of expression of tumor antigens in healthy tissues. We leveraged in vivo target expression and toxicity data of TCBs targeting folate receptor 1 (FOLR1) or carcinoembryonic antigen (CEA) to design and validate human immunocompetent Organs-on-Chips safety platforms. We discovered that the Lung-Chip and Intestine-Chip could reproduce and predict target-dependent TCB safety liabilities, based on sensitivity to key determinants thereof, such as target expression and antibody affinity. These novel tools broaden the research options available for mechanistic understandings of engineered therapeutic antibodies and assessing safety in tissues susceptible to adverse events.

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“…9 On-target deployment may be skewed by dispersion of ACT products caused by trapping in the pulmonary circulation, sequestration in the reticuloendothelial system (RES), extravasation into interstitial spaces, 'cellular sinks' for homeostatic cytokines or the immune-suppressive effect of the tumor-bearing status. [10][11][12][13][14] Critchley-Thorne et al 15 observed that the response of circulating lymphocytes to interferon (IFN) stimulation is frequently dampened in patients with cancer. The degree of dysfunction is patientspecific, determined by an indirect effect of cancer cell bioproducts 16 and it is reversible ex vivo.…”

Section: Timentioning

confidence: 99%

“…We propose that this differential is a key TME-specific crossroad determining theTI in solid malignancies ( figure 1 ). For instance, Castellarin et al 14 developed an immune-deficient mouse model expressing human HER2 in normal hepatic tissue. On-target/off-tumor toxicity was compared between two affinity-tuned HER2-specific CAR-T cells.…”

Section: Tme-specific Factorsmentioning

confidence: 99%

“…Fine tuning of CAR affinity may reduce on-target/off-tumor effects. 14 42 Dual targeting of antigens co-expressed by tumor cells may either increase specificity or decrease chances for tumor escape according to the conditionality of their activation: if both antigens are required for full CAR-T cell activation specificity for neoplastic tissues is enhanced while if either one is sufficient for activation tumor escape will occur only with both antigens’ expression is lost but specificity will be dampened. Two CAR constructs can be included into the same product.…”

Section: Combinatorial Approaches To Increase the Timentioning

confidence: 99%

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Improving the therapeutic index in adoptive cell therapy: key factors that impact efficacy

Wang

Cesano

Butterfield³

et al. 2020

J Immunother Cancer

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The therapeutic index (TI) is a quantitative assessment of a drug safety proportional to its effectiveness. The estimation is intuitive when the engagement of the product with its target is dependent on stable chemistry and predictable pharmacokinetics as is the case for small molecules or antibodies. But for therapeutics with complex biodistribution and context-dependent potency such as adoptive cell therapy (ACT) products, TI estimations need to consider a broader array of factors. These include product-dependent variability such as functional fitness, unpredictable pharmacokinetics due to non-specific trapping, sequestration and extravasation into normal tissues and variable rates of in vivo expansion. In the case of solid malignancies, additional modifiers dependent on individual tumor immune biology may affect pharmacodynamics, including differential trafficking to benign compared with cancer tissue, hampered engagement with target cells, immune suppression and cellular dysfunction due to unfavorable metabolic conditions. Here, we propose a patient-specific assessment of factors affecting on-tumor from off-tumor activity in disparate immunologic environments that impact ACT’s clinical efficacy and may favorably balance the TI. for ACT products.

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A rational mouse model to detect on-target, off-tumor CAR T cell toxicity

Cited by 67 publications

References 51 publications

Human immunocompetent Organ-on-Chip platforms allow safety profiling of tumor-targeted T-cell bispecific antibodies

Human immunocompetent Organ-on-Chip platforms allow safety profiling of tumor-targeted T-cell bispecific antibodies

Human immunocompetent Organ-on-Chip platforms allow safety profiling of tumor-targeted T-cell bispecific antibodies

Improving the therapeutic index in adoptive cell therapy: key factors that impact efficacy

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