Coordinating Cellular Response to Create More Durable Cancer Immunotherapies

Groundbreaking research in multi-omics has transformed the immunotherapy landscape, leading to an increased understanding of the mechanisms and pathways that regulate the immune system’s response to cancer. However, in spite of these advances, barriers still exist for the field of cancer immunotherapy—from confirming the function of engineered therapies after editing to improving the safety, efficacy, and long-term durability of novel therapies.1,2

Functional single-cell and bulk proteomics have provided a solution for many of these challenges, enabling researchers to characterize the function of immune cells and the quality of therapeutic products with deeper access to in vivo biology.2

Functional Cell Library provides insight into new cell types identified by functional phenotyping

IsoPlexis has developed a technology able to phenotype each individual immune cell by its extracellular function. This method, also known as functional phenotyping, overcomes these  critical challenges by functionally defining each T cell, monocyte, and NK cell.

Functional phenotyping can help researchers fine-tune their immunotherapeutic candidates and identify what differentiates immune cell potency, cell product toxicity, and the functional differences between responsive and nonresponsive patients. With IsoPlexis’ unique Functional Cell Library (FCL), a set of key proteomically active cells,  a new and unique layer of proteomic data characterizing the superpowered drivers of immune response has been uncovered. By identifying and profiling these superpowered cell types, IsoPlexis provides new insights into the drivers of response and the pathways essential for creating successful cancer immunotherapies. The FCL also covers a variety of engineered cell types to meet the needs of the rapidly expanding cell therapy space. In addition to autologous and allogeneic CAR-T cells and TILs, the FCL includes natural killer (NK) cells, T-cell receptor transgenic T cells (TCR-T), and various types of monocytes. This provides researchers with data across a comprehensive range of cell therapy product types.3

Because every immune cell is different, the complete characterization of each individual cell is critical. Most immune cells secrete one cytokine, or sometimes none, but some immune cells have the ability to secrete multiple cytokines simultaneously, known as polyfunctionality. The presence of these unique, highly polyfunctional “superhero” cells correlates with anti-tumor activity, therapy persistence, and more in several high-impact studies.

Proprietary Single-Cell Proteomic Barcoding Platform: Powerful Biology

The IsoPlexis platform has the unique ability to identify polyfunctional subsets of cells which affect outcomes such as persistence and durability of response, patient stratification, tumor resistance, toxicity, and immune suppression. Unlike bulk averaging alone, the addition of single-cell proteomics allows for more precise analysis of these highly polyfunctional superhero cells, which can be predictive of patients’ clinical outcomes.

Using IsoPlexis’ platform, both single-cell and multiplexed bulk proteomic experiments are fully automated, with data sent directly to the IsoSpeak software for analysis. IsoPlexis’ Proteomic Barcoded IsoCode Chips are used to detect 30+ cytokines per cell, measuring the functional phenotype of each immune cell. With the IsoLight system, a process that would traditionally require multiple instruments and steps, is accomplished in one instrument with a variety of chip options to suit a wide range of research needs.

Identifying Key Biomarkers of Cellular Response to Improve Durability of Cell Therapies

Studies have demonstrated that single-cell functional profiling and polyfunctionality can reveal predictive insights across the entire cell therapy development pipeline, from confirming the function of gene edits and identifying prime candidates to optimizing cell therapy manufacturing and revealing predictive biomarkers for patient outcomes.

Throughout the CAR-T development process, predictive biomarkers allow researchers to stratify patient response to therapy and identify those with an increased risk of adverse side eff­ects. IsoPlexis’ polyfunctional biomarker is a powerful predictive metric which has correlated in various studies to therapy response.4

High Impact Use Cases Leverage Unique Single-Cell Proteomic Analysis

To improve cell therapies, researchers must understand how these types of therapeutics work, as early as possible. In two recent publications, scientists leveraged IsoPlexis’ single-cell proteomics analysis technology to gain improved assessments of cell therapy quality, potency, and durability.5

In a paper recently published in the Journal of Clinical Oncology6, researchers presented results from the international, single-arm PIVOT-02 study in which they evaluated the CD122-preferential interleukin-2 pathway agonist bempegaldesleukin (BEMPEG) plus nivolumab (NIVO) in first-line metastatic melanoma. Results showed that BEMPEG in combination with NIVO was tolerated, with relatively low rates of grade 3 and 4 treatment-related and immune-mediated adverse events. The combination had encouraging anti-tumor activity including an extended median progression-free survival. These data suggest that NIVO/BEMPEG combination therapy may be safe and effective as a treatment for metastatic melanoma, and provide rational for the ongoing Phase II study in this same patient population.

In this study, IsoPlexis’ polyfunctional strength index (PSI) was a key metric that effectively predicted overall patient response rate.7 The predictive blood-based biomarker identified by IsoPlexis’ platform enabled the team to evaluate patient response to the therapy after eight days of treatment, far earlier than was previously possible.7

Additionally, a study published in Nature Medicine titled, “CAR T cells with dual targeting of CD19 and CD22 in adult patients with recurrent or refractory B cell malignancies: a phase 1 trial,”8 leveraged IsoPlexis’ platform to  identify early indicators of response or relapse in CAR-T therapy.

In the Phase 1 clinical trial in patients with relapsed B cell acute lymphoblastic leukemia (B-cell ALL) and LBCL, IsoPlexis’ unique single-cell functional proteomics provided meaningful product quality insights to predict CAR potency in vivo. The data from the trial suggest that progressive disease after CD19-22.BB.z-CAR in LBCL is associated with a robust early response followed by early acquired resistance. Researchers identified a functional driver of relapse suggesting possible improvements in CAR manufacturing that could prevent antigen+ resistance. The study highlights how IsoPlexis is providing critical predictive metrics for the product characterization and optimization of CAR-T therapies and manufacturing workflows.9

Conclusion

Functional single-cell and bulk proteomics have addressed the urgent challenges involved in understanding and overcoming the complexity of tumor-immune reaction. IsoPlexis’ single-cell proteomic platform addresses the core problem that immune cells, which play a major role in cancer immunology, are heterogenous. With IsoPlexis’ comprehensive library of proteomically active cells, researchers now have the resources to fine-tune their immunotherapeutic candidates and identify what differentiates immune cell potency, cell product toxicity, and functional differences between patient responders and non-responders to immunotherapies.

References

  1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5521300/
  2. https://isoplexis.com/blog/expert-panel-discussion-advances-in-cell-and-immunotherapies-in-treating-cancer/
  3. https://isoplexis.com/webinars/integrating-single-cell-transcriptomics-proteomics/watch/?submissionGuid=bf400a2f-dbd1-4bc6-8551-2bf1a7dd0c22
  4. https://isoplexis.com/blog/single-cell-functional-biomarkers-for-each-stage-of-the-cell-therapy-development-pipeline/
  5. https://investors.isoplexis.com/news-releases/news-release-details/isoplexis-expanded-cell-therapy-offerings-demonstrated-nature
  6. Diab, Adi et al. Bempegaldesleukin Plus Nivolumab in First-Line Metastatic Melanoma. Journal of Clinical Oncology 39, no. 26 (September 10, 2021) 2914-2925. DOI: 10.1200/JCO.21.00675
  7. https://www.genengnews.com/sponsored/single-cell-proteomics-predicts-progression-free-survival-in-melanoma-study/
  8. Spiegel, J.Y., Patel, S., Muffly, L. et al.CAR T cells with dual targeting of CD19 and CD22 in adult patients with recurrent or refractory B cell malignancies: a phase 1 trial. Nat Med27, 1419–1431 (2021). https://doi.org/10.1038/s41591-021-01436-0
  9. https://isoplexis.com/blog/published-in-nature-medicine-overcoming-critical-challenges-in-cell-therapy-manufacturing-with-isoplexis-technology/

 

Share This Article
Subscribe to Follow the Data

Weekly email to keep you at the forefront of single-cell & multiplexed proteomics.