Publication Overview: Single-Cell Proteomics in Persistence and Overcoming Antigen Escape in New Leukemia Publication

Recently, IsoPlexis’ single-cell functional phenotyping was highlighted in a publication in Leukemia (a Nature publication), “CAR T-cells that target acute B-lineage leukemia irrespective of CD19 expression.” IsoPlexis’ platform enabled researchers to predict which T cell therapies produced persistent results in difficult to treat situations, such as antigen escape. It had previously been reported that similar data in multiple myeloma (published in Blood Advances).

Researchers sought to find a solution for the estimated 39% of BL-ALL patients who relapse after CD19-directed therapies. In pre-clinical settings for both solid and liquid tumors, combinatorial CAR-T cell therapies have demonstrated a clear advantage. While CD19 is the usual target for BL-ALL due to it being ubiquitously expressed, “CD20 is expressed in about 50% of cases and CD22 is expressed in about 80-90%”1 of cases. And, CD20 is expressed by 40-50% of patients who have mature B-lymphoid neoplasms, which are typically associated with a poor prognosis, and when present at diagnosis is a predictor of relapse when it comes to adult patients. Antibody therapies targeting CD20 are now being used as front-line therapy for adults with BL-ALL.1

Researchers Fousek et al. designed a therapy to target multiple antigens that could either be used as a secondary, salvage therapy, or as an initial CAR-T therapy.1 The IsoPlexis platform was used to characterize the novel cell therapy products for effectiveness and potency.

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Highlighted findings from this study:

  • Single-cell functional proteomics revealed the enhanced polyfunctional profiles of CD19/20/22CAR-T cells with the robust anti-tumor activity in response to CD19+ and CD19- tumor cells, supporting a potential advantage of CD19/20/22CAR as salvage or front-line CAR therapy for patients with recalcitrant disease such as CD19-escape BL-ALL.
  • Importantly, the IsoCode chip demonstrated a marked upregulation of antigen-specific polyfunctionality in CD19/20/22CAR T cells compared to CD19CAR-T cells, which correlated with their both short and long-term in vitro superior cytolytic capabilities to tumor cells.
  • Polyfunctional CD19/20/22CAR-T cells exhibit a greater formation of a functional chimeric antigen receptor immune synapse (CARIS) with both CD19- and CD19+ tumor cells, which could enhance their immunoactivity and prolong tumor-killing ability.
  • Polyfunctional CD19/20/22CAR-T cells effectively target both CD19+ and CD19- B-lineage acute lymphoblastic leukemia (BL-ALL) and demonstrate superior anti-leukemic activity in vivo against CD19- and CD19+ BL-ALL.

This construct was also found to be more activated when encountering target antigens (CD19+, CD20+, CD22) when compared with CD19CAR-T cells. “Only CD19/20/22CAR-T cells maintained CD20 and CD22 CAR expression and consequently their activity against these target molecules.”1 When this novel CAR-T product was tested in a long-term killing assay, the CD19/20/22CAR-T cells “eliminated target cells more promptly and sustained this affect over 5 days of testing.”1 IsoPlexis’ platform has identified persistence now in several publications, which has correlated to an increase in anti-tumor activity.

Increased Polyfunctionality and Improved Binding and Efficacy of Next Generation Trimeric CAR-T Construct

In a study with researchers at Massachusetts General Hospital, IsoPlexis’ technology predicted persistence and overcoming antigen escape in treating multiple myeloma (MM). “Rational design of a trimeric APRIL-based CAR-binding domain enables efficient targeting of multiple myeloma” was published in Blood Advances, a summary of which can be found here. Researchers in this study developed a novel construct to target both BCMA and TACI antigens that would lead to improved binding and efficacy against MM. Researchers Schmidts et al. utilized IsoPlexis’ platform to characterize their novel construct. With this, they observed enhanced binding to both antigens, enhanced activity, and upregulated polyfunctionality, which correlated with tumor killing in human and mouse models when compared to a monomeric construct.

The type of construct in this study proves to be a “promising therapeutic approach for MM” with the potential to prevent as well as treat BCMA escape. IsoPlexis’ single-cell functional biology was able to provide the data to help researchers determine functional differences between this unique CAR construct and other CARs. This helped to verify that this novel construct holds promise for the treatment of MM.

To speak with a functional cellular proteomics expert on how IsoPlexis’ platform can help accelerate your therapy program, click here. Learn more about what IsoPlexis’ Single-Cell Polyfunctional Strength solution can do for you by downloading the product sheet here.

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