# Therapeutic Potential of CAR-CIK Cells in Acute Leukemia Relapsed Post Allogeneic Stem Cell Transplantation

## TL;DR

CAR-CIK cells are a promising new therapy for treating leukemia relapse after stem cell transplants, offering strong anti-leukemia effects with less risk of harmful side effects.

## Contribution

The novel integration of CAR technology into CIK cells offers a new therapeutic platform with reduced toxicity and enhanced efficacy for post-transplant leukemia relapse.

## Key findings

- CAR-CIK cells combine CIK biology with CAR engineering to enhance graft-versus-leukemia effects while reducing graft-versus-host disease.
- CAR-CIK therapy shows promise in treating B-cell ALL and AML relapsed after allogeneic stem cell transplantation.
- CIK cells exhibit low toxicity and MHC-unrestricted antitumor activity, making them a safer alternative to traditional donor lymphocyte infusions.

## Abstract

Adoptive cellular therapy has long been viewed as an attractive strategy to prevent and treat post-transplant relapse in acute leukemia. Donor lymphocyte infusions (DLIs) remain the conventional approach, offering clear graft-versus-leukemia (GVL) activity but at the cost of a significant risk of graft-versus-host disease (GvHD). Cytokine-induced killer (CIK) cells have recently emerged as an alternative, retaining robust GVL effects while generally inducing less GvHD. Building on these advantages—and inspired by the clinical success of CAR T-cell therapies in B-cell malignancies—a new platform has been developed: CAR-CIK cells, which integrate CIK biology with chimeric antigen receptor engineering to enhance efficacy with reduced toxicity. This review summarizes the key clinical data on CAR-CIK therapy for managing post-transplant relapse in B-cell acute lymphoblastic leukemia and acute myeloid leukemia.

Adoptive cellular therapy with donor-derived T cells has always been an attractive strategy after allogeneic hematopoietic stem cell transplantation (allo-HSCT) to reduce the risk of relapse in acute myeloid and lymphoid leukemias. Donor lymphocyte infusion (DLI) is still the best-established option, especially in the preemptive phase when measurable residual disease (MRD) becomes positive and in the prophylactic setting—when MRD is not detectable. However, the clinical benefit of DLI is counterbalanced by the possible onset of graft-versus-host disease (GvHD), which continues to restrict its wide application. To address this challenge, several alternative cell-based strategies have been developed. One of these is represented by cytokine-induced killer (CIK) cells, generated from donor peripheral blood mononuclear cells through stimulation with anti-CD3 antibodies, interferon-γ, and interleukin-2. These cells are characterized by a hybrid phenotype, combining T-cell functions with natural killer-like properties, and exhibit antitumor activity in an MHC-unrestricted manner. CIK cells are generally well tolerated and associated with low toxicity but their efficacy is so far modest. Based on the experience of CAR-T in the treatment of B-cell lymphoid disease, CIK cells have been engineered with chimeric antigen receptors (CAR) developing the CARCIK cells. This novel cellular strategy represents a promising approach in the treatment of acute myeloid and lymphoid leukemia relapsed post-allo-HSCT. This review provides an overview of the current CAR-CIK experiences in the setting of acute leukemias and outlines future directions for their clinical translation.