Provided are methods and compositions for obtaining functionally enhanced derivative effector cells obtained from directed differentiation of genomically engineered iPSCs. The derivative cells provided herein have stable and functional genome editing that delivers improved or enhanced therapeutic effects. Also provided are therapeutic compositions and the used thereof comprising the functionally enhanced derivative effector cells alone, or with antibodies or checkpoint inhibitors in combination therapies.

Provided herein are compositions and methods for genetically engineering a cell (e.g., a hematopoietic cell) to modify a gene encoding a lineage-specific cell-surface antigen to modify an epitope of the lineage-specific cell-surface antigen recognized by an agent. Also provided are methods involving administering such genetically engineered cells to a subject, such as a subject having a hematopoietic malignancy, as well as the genetically engineered cells themselves.

Compositions and methods for editing, e.g., altering a DNA sequence, within a CD38 gene are provided. Compositions and methods for immunotherapy are provided.

Disclosed are compositions and methods for treating cancers characterized by the presence of solid tumors, which simultaneously target a plurality of targets on cancer cells using single CAR T construct.

CD38 is also expressed in a variety of malignant hematological diseases, including multiple myeloma. In the present invention, the inventors have generated a new antibody against CD38 that could be suitable for producing bispecific antibodies as well as CAR-T cells. In particular, the inventors report the development of Bi38-3, a new bispecific T cell engager that targeted CD38 on MM cells and recruited cytotoxic T cells through the CD3. Bi38-3 lacked the Fc region of natural mAb, which contributes to resistance processes, but triggered T cells to proliferate, release cytokine and lyse CD38 positive MM cells in vitro. Similarly, Bi38-3 induced autologous T cells to eliminate tumor plasma cells isolated from MM patients both at diagnosis and at relapse. The cytotoxicity triggered by Bi38-3 was restricted to cells expressing high levels of CD38 and preserved the integrity of T, B and NK lymphocytes in vitro. Importantly, Bi38-3 rapidly reduced tumor cells in an MM1.S xenograft mouse model of human MM. Taken together, the results show that the antibody of the present invention is an effective reagent to specifically eliminate CD38 positive malignant cells without significantly affecting CD38 lowly expressing cells and represents a promising novel immunotherapeutic tool for the treatment of malignant hematological diseases, and especially multiple myeloma.

Disclosed herein are engineered natural killer cells that have been modified to express chimeric antigen receptors (CARs). The cells optionally contain other modifications that improve tumor specific cytotoxicity and homing to tumor sites. Also contemplated are methods for using the engineered natural killer cells to treat patients with cancer.

Genetically engineered cells (e.g., HSPCs or T cells), such as hematopoietic stem cells, having one or more genetically edited genes of cell-surface proteins, and therapeutic uses thereof, either alone or in combination with immune therapy that targets the cell-surface protein(s).

Immunotherapeutic Monoclonal Antibody Complexes or Conjugates (IMAC) comprising readily accessible antibodies designed and approved for clinical use are provided using a one-step method that combines killing of existing cancer cells in parallel with induction of long-lasting anti-cancer vaccination. Methods for their use, alone or in combination with cancer killer cells including intentionally mismatched donor T cells, NK cells concomitantly with additional anti-cancer or immune activating agents, or activation of patient's own immune system for personalized treatment of cancer and elimination of undesirable non-malignant cells are also provided. In addition, treatment method based on IMAC can be applied for in vivo vaccination against cancer using an existing malignant lesion as internal anti-cancer vaccine by engagement of patients antigen presenting cells for induction of long-lasting anti-cancer vaccination in situ against residual or recurrent disease.