Over the past two decades, antigen-directed immunotherapies such as monoclonal antibodies (mAbs), antibody-drug-conjugates (ADCs), bispecific T cell engagers (BTEs), or chimeric antigen receptor T cells (CAR-T cells) have revolutionized medical oncology. These therapies redirect immune cell cytotoxicity towards cancer cells by precisely targeting cell surface molecules called antigens. However, identifying antigens that are uniquely expressed on cancer cells has been difficult because cancer cells originate from normal cells and therefore share many antigens with them. This has limited current therapeutic approaches to targeting a limited number of shared antigens with acceptable off-tumor toxicity and has culminated in a very fragmented approach to drug development. To address this, an epitope-edited hematopoietic stem cell and CAR-T cell immunotherapy pair was developed that enables the targeting of the pan-leukocyte marker CD45 without off-tumor toxicity. Epitope mapping followed by targeted CRISPR base editing generated a CD45 variant that evades CAR-T cell recognition while preserving CD45 expression and function. Epitope-editing in human T cells enabled CD45 CAR T cell expansion that were efficacious against diverse types of blood cancer. In hematopoietic stem cells (HSC), epitope-editing facilitated regeneration and persistence of a healthy hematopoietic system in the presence of ongoing CD45 CAR T cell activity against cancer cells. The CD45 epitope engineered HSC and CD45 CAR T cell pair enables the safe and effective use of CD45-directed CAR T cells for most hematologic malignancies. In addition, epitope editing also protected cells from BTEs demonstrating that this platform is agnostic to therapeutic modality. Furthermore, the CD45 platform was harnessed for eradication of latent cellular HIV reservoirs by multiplex base editing CD45 and CCR5 to achieve resistance to both CD45 CAR T cells and HIV infection, demonstrating the versatility of this platform for other diseases of hematopoietic origin.