Low-affinity CAR T cells exhibit reduced trogocytosis, preventing rapid antigen loss, and increasing CAR T cell expansion

Olson, Michael; Mause, Erica R. Vander; Radhakrishnan, Sabarinath Venniyil; Brody, Joshua; Rapoport, Aaron P.; Welm, Alana L.; Atanackovic, Djordje; Luetkens, Tim

doi:10.1038/s41375-022-01585-2

Cited by 46 publications

(35 citation statements)

References 15 publications

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“…This finding may be related to the overexpression of CJUN together with FH9Q or more physiological T cell stimulation by low affinity CAR constructs 13 , but could also be the result of reduced trogocytosis by low affinity CAR T cells, which we have previously shown to enhance CAR T cell persistence 30 . Trogocytosis is the stripping of target antigen together with target cell membrane and their incorporation into the CAR T cell membrane, resulting in antigen negative tumor cells and antigen-positive CAR T cells 30, 31 , potentially leading to fratricide, the killing of CAR T cells by other CAR T cells. We therefore determined the level of membrane transferred from MM cells to CAR T cells in a short-term co-culture.…”

Section: Resultsmentioning

confidence: 81%

Combinatorial T cell engineering eliminates on-target off-tumor toxicity of CD229 CAR T cells while maintaining anti-tumor activity

Mause

Baker

Radhakrishnan

et al. 2021

Preprint

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T cells expressing chimeric antigen receptors have shown remarkable therapeutic activity against different types of cancer. However, their wider use has been hampered by the potential for life-threatening toxicities due to the unintended targeting of healthy cells expressing low levels of the targeted antigen. We have now developed an affinity-tuning approach for the generation of minimally modified, low-affinity antibody variants derived from existing high-affinity antibodies. Using this approach, we engineered a low affinity variant of the fully human CD229-specific antibody 2D3. Parental 2D3 efficiently targeted multiple myeloma cells but also healthy T cells expressing low levels of CD229. We demonstrate that CAR T cells based on a low affinity variant of 2D3 maintain the parental antibody's anti-tumor activity, but lack its targeting of healthy T cells. In addition, variant CD229 CAR T cells show reduced trogocytosis potentially augmenting CAR T cell persistence. The fast off-rate CAR produced using our affinity tuning approach eliminates a key liability of CD229 CAR T cells and paves the way for the effective and safe treatment of patients with multiple myeloma.

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Section: Resultsmentioning

confidence: 81%

Combinatorial T cell engineering eliminates on-target off-tumor toxicity of CD229 CAR T cells while maintaining anti-tumor activity

Mause

Baker

Radhakrishnan

et al. 2021

Preprint

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“…Trogocytosis also cause tumor escape due to antigen loss on target cells. For example, the CD19 CARTs based on high-affinity FMC63 mAb had higher trogocytosis and fratricide than the CD19 CARTs from a lower-affinity CAT mAb ( 158 , 159 ). 3) The strong and persistent engagement of high avidity CARTs with tumor cells may drive CARTs to exhaustion and activation-induced cell death (AICD).…”

Section: The Effects Of Abd Affinity On the Biology And Function Of C...mentioning

confidence: 98%

The affinity of antigen-binding domain on the antitumor efficacy of CAR T cells: Moderate is better

Mao

Kong

2022

Front. Immunol.

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The overall efficacy of chimeric antigen receptor modified T cells (CARTs) remain limited in solid tumors despite intensive studies that aim at targeting multiple antigens, enhancing migration, reducing tonic signaling, and improving tumor microenvironment. On the other hand, how the affinity and engaging kinetics of antigen-binding domain (ABD) affects the CART’s efficacy has not been carefully investigated. In this article, we first analyzed 38 published solid tumor CART trials and correlated the response rate to their ABD affinity. Not surprisingly, majority (25 trials) of the CARTs utilized high-affinity ABDs, but generated merely 5.7% response rate. In contrast, 35% of the patients treated with the CARTs built from moderate-affinity ABDs had clinical responses. Thus, CARTs with moderate-affinity ABDs not only have less off-target toxicity, but also are more effective. We then reviewed the effects of ABD affinity on the biology and function of CARTs, providing further evidence that moderate-affinity ABDs may be better in CART development. In the end, we propose that a fast-on/fast-off (high Kon and Koff) kinetics of CART-target engagement in solid tumor allow CARTs to generate sufficient signaling to kill tumor cells without being driven to exhaustion. We believe that studying the ABD affinity and the kinetics of CART-tumor interaction may hold a key to designing effective CARTs for solid tumors.

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“…However, at the dawn of the CAR-T technology development, significant efforts were directed to obtaining receptors with high affinity [ 110 ]. Later, it was found that the use of CARs with low micromolar affinity can provide excellent antitumor efficacy and high safety with a low risk of systemic non-tumor toxicity compared to high-affinity CARs [ 111 , 112 , 113 , 114 ]. This was explained by the low specificity of CAR-T cells with high nanomolar affinity, which resulted in their nonspecific activation and the occurrence of systemic toxicity or a complete lack of effect [ 113 ].…”

Section: Practical Valuementioning

confidence: 99%

The Enigmatic Nature of the TCR-pMHC Interaction: Implications for CAR-T and TCR-T Engineering

Shevyrev

Tereshchenko

Sennikov

2022

IJMS

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The interaction of the T-cell receptor (TCR) with a peptide in the major histocompatibility complex (pMHC) plays a central role in the adaptive immunity of higher chordates. Due to the high specificity and sensitivity of this process, the immune system quickly recognizes and efficiently responds to the appearance of foreign and altered self-antigens. This is important for ensuring anti-infectious and antitumor immunity, in addition to maintaining self-tolerance. The most common parameter used for assessing the specificity of TCR-pMHC interaction is affinity. This thermodynamic characteristic is widely used not only in various theoretical aspects, but also in practice, for example, in the engineering of various T-cell products with a chimeric (CAR-T) or artificial (TCR-engineered T-cell) antigen receptor. However, increasing data reveal the fact that, in addition to the thermodynamic component, the specificity of antigen recognition is based on the kinetics and mechanics of the process, having even greater influence on the selectivity of the process and T lymphocyte activation than affinity. Therefore, the kinetic and mechanical aspects of antigen recognition should be taken into account when designing artificial antigen receptors, especially those that recognize antigens in the MHC complex. This review describes the current understanding of the nature of the TCR-pMHC interaction, in addition to the thermodynamic, kinetic, and mechanical principles underlying the specificity and high sensitivity of this interaction.

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Low-affinity CAR T cells exhibit reduced trogocytosis, preventing rapid antigen loss, and increasing CAR T cell expansion

Cited by 46 publications

References 15 publications

Combinatorial T cell engineering eliminates on-target off-tumor toxicity of CD229 CAR T cells while maintaining anti-tumor activity

Combinatorial T cell engineering eliminates on-target off-tumor toxicity of CD229 CAR T cells while maintaining anti-tumor activity

The affinity of antigen-binding domain on the antitumor efficacy of CAR T cells: Moderate is better

The Enigmatic Nature of the TCR-pMHC Interaction: Implications for CAR-T and TCR-T Engineering

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