Abstract
Adoptive immunotherapy with antibody-based therapy or with T cells transduced to express chimeric antigen receptors (CARs) is useful to the extent that the cell surface membrane protein being targeted is not expressed on normal tissues. The most successful CAR-based (anti-CD19) or antibody-based therapy (anti-CD20) in hematologic malignancies has the side effect of eliminating the normal B cell compartment. Targeting solid tumors may not provide a similar expendable marker. Beyond antibody to Her2/NEU and EGFR, very few antibody-based and no CAR-based therapies have seen broad clinical application for solid tumors. To expand the way in which the surfaceome of solid tumors can be analyzed, we created an algorithm that defines the pairwise relative overexpression of surface antigens. This enables the development of specific immunotherapies that require the expression of two discrete antigens on the surface of the tumor target. This dyad analysis was facilitated by employing the Hotelling’s T-squared test (Hotelling–Lawley multivariate analysis of variance) for two independent variables in comparison to a third constant entity (i.e., gene expression levels in normal tissues). We also present a unique consensus scoring mechanism for identifying transcripts that encode cell surface proteins. The unique application of our bioinformatics processing pipeline and statistical tools allowed us to compare the expression of two membrane protein targets as a pair, and to propose a new strategy based on implementing immunotherapies that require both antigens to be expressed on the tumor cell surface to trigger therapeutic effector mechanisms. Specifically, we found that, for MYCN amplified neuroblastoma, pairwise expression of ACVR2B or anaplastic lymphoma kinase (ALK) with GFRA3, GFRA2, Cadherin 24, or with one another provided the strongest hits. For MYCN, non-amplified stage 4 neuroblastoma, neurotrophic tyrosine kinase 1, or ALK paired with GFRA2, GFRA3, SSK1, GPR173, or with one another provided the most promising paired-hits. We propose that targeting these markers together would increase the specificity and thereby the safety of CAR-based therapy for neuroblastoma.
Highlights
The field of immunotherapy has entered a time of rapid advancement
Using the data analysis pipeline described in Section “Materials and Methods,” and illustrated in Figure 1, we set the final parameter of Log FKPM in any vital organ at 1.0, and received a readout of 325 unique gene pairs; comprised of 26 unique genes for MYCN-A neuroblastoma and 528 unique gene pairs, comprised of 33 unique genes, for MYCN-NA neuroblastoma
In previous work to define transcripts overexpressed in pediatric solid tumors, we were struck by the difficulty in finding antigens that are overexpressed on tumor cells but not on normal tissue, and able to serve as therapeutic targets
Summary
Built upon decades of basic research, the fields of recombinant protein engineering, high-throughput screening, and gene vector biology, have allowed the implementation of engineered immunoglobulin molecules and engineered immune cells in clinically meaningful protocols. This is especially true for hematologic malignancies. Antibodies featuring engineered Fc domains or bispecific antibodies are considered part of our current armamentarium for leukemia expressing CD19 or CD20 [1,2,3]; as are T cells engineered to express chimeric antigen receptors (CARs) that target CD19 [4, 5]. The targeting of B cell malignancies by these agents eliminates normal mature B lymphocytes, which is a well-tolerated “on-target” side-effect. The ability to use these approaches in conjunction with hematopoietic stem cell transplantation can take patients who are complete responders, and who may yet relapse, into the realm of true “cure” [6]
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