Is Hematopoietic Stem Cell Transplantation Required to Unleash the Full Potential of Immunotherapy in Acute Myeloid Leukemia?

Abstract

From monoclonal antibodies (mAbs) to Chimeric Antigen Receptor (CAR) T cells, immunotherapies have enhanced the efficacy of treatments against B cell malignancies. The same has not been true for Acute Myeloid Leukemia (AML). Hematologic toxicity has limited the potential of modern immunotherapies for AML at preclinical and clinical levels. Gemtuzumab Ozogamicin has demonstrated hematologic toxicity, but the challenge of preserving normal hematopoiesis has become more apparent with the development of increasingly potent immunotherapies. To date, no single surface molecule has been identified that is able to differentiate AML from Hematopoietic Stem and Progenitor Cells (HSPC). Attempts have been made to spare hematopoiesis by targeting molecules expressed only on later myeloid progenitors as well as AML or using toxins that selectively kill AML over HSPC. Other strategies include targeting aberrantly expressed lymphoid molecules or only targeting monocyte-associated proteins in AML with monocytic differentiation. Recently, some groups have accepted that stem cell transplantation is required to access potent AML immunotherapy and envision it as a rescue to avoid severe hematologic toxicity. Whether it will ever be possible to differentiate AML from HSPC using surface molecules is unclear. Unless true specific AML surface targets are discovered, stem cell transplantation could be required to harness the true potential of immunotherapy in AML.

Cell-based and antibody-mediated immunotherapies directed against leukemic stem cells in acute myeloid leukemia: Perspectives and open issues

“…48,82 One recurrent problem seems to be a cytokine is hope that more specific and more effective CAR-T cell based approaches will be developed for AML patients in the future. 82,[107][108][109][110][111][112][113][114][115][116][117] However, several issues and limitations have to be taken into tional "on-target but off-leukemia" toxicities. One major problem is prolonged myelotoxicity especially when the CAR-T approach will also eliminate normal stem cells.…”

“…One major problem is prolonged myelotoxicity especially when the CAR-T approach will also eliminate normal stem cells. 82,[107][108][109][110][111][112][113][114][115][116][117] This problem may occur with CAR-T cells directed against diverse stem cell antigens, including CD33. Several strategies have been proposed to overcome this form of toxicity.…”

“…One is to combine the CAR-T cell approach with HSCT. 117 A futuristic idea is to genetically inactivate CD33 in hematopoietic stem cells to enable application of CD33-directed CAR-T cell therapy. 118 Another important issue in CAR-based AML therapy is that current approaches are not addressing the diversity and the related clonal complexity of AML LSC, but rather focus on only one or two cell surface targets.…”

“…118 Another important issue in CAR-based AML therapy is that current approaches are not addressing the diversity and the related clonal complexity of AML LSC, but rather focus on only one or two cell surface targets. [107][108][109][110][111][112][113][114][115][116][117] In this regard, it is important to recognize that AML LSC are heterogeneous cells with varying combinations of cell surface antigens and target structures. [14][15][16]82 Since all of these subclones can theoretically cause a relapse, it might be of utmost importance to develop poly-targeted CAR-T or CAR-NK cell strategies.…”

“…However, only three patients responded, and after a couple of months (1‐23 months) all patients relapsed. Other CAR‐T cell‐based therapies are currently being prepared in AML in preclinical studies or are tested in phase I clinical trials 82,107‐117 . Based on the observation that AML LSC display aberrantly expressed cell surface target antigens and the encouraging preclinical data with CAR‐T cells recognizing CD123, CLL‐1, FLT3, and other surface molecules, there is hope that more specific and more effective CAR‐T cell based approaches will be developed for AML patients in the future 82,107‐117 …”