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K.D. Cummins et al.
Figure 1. A proposed design for a novel therapeutic platform for acute myeloid leukemia (AML), combining hematopoietic stem and progenitor cell (HSPC)- CD33KO with CD33-directed chimeric antigen receptor-modified T cell (CART33) therapy. CART33 manufacture is performed at steady state, prior to mobilization agents that may affect the composition of the resultant CART product. CART33 and HSPC-CD33KO will be from the same allogeneic donor. Sex difference between donor and patient are shown only to demonstrate an allogeneic donor for the purpose of this diagram. KO: knock-out. RR AML: relapsed/refractory AML; AlloCART- 33: anti CD33 CAR T-cell, made from allogeneic donor cells; HSPC-CD33KO: hematopoietic stem/progeitor cells with CD33 knock-out; alloHSCT: allogeneic hematopoietic stem/progenitor cell transplant.
A unique advantage of TCR-T over CAR-T is their abil- ity to recognize intracellular antigens that are presented on the MHC of cancer cells, thus theoretically increasing their anti-tumor specificity. While AML has a relatively low mutational burden of AML, and thus relatively few neoantigens that could be targeted,37 a possibly viable tar- get is the TAA tumor-associated antigen Wilms’ tumor 1 (WT1).38 Several groups have demonstrated safety and a measure of efficacy in early phase trials of patients with AML/MDS, though disease responses were transient.39,40 A new phase I/II trial evaluating WT1 TCR-T in combi- nation with IL-2 in patients with AML/MDS was recently completed (clinicaltrials.gov identifier: 02550535) and the results are eagerly awaited.
Given the enormous efforts to drug the PD/PDL1 axis in solid cancers, interest has also turned to this approach in AML. PD-L1 was shown to be up-regulated on blasts in an analysis of 55 samples selected for their high white cell count, with the hypothesis that up-regulated PD-L1 was coupled with leukocytosis due to failure of the immune response.41 However, PD1-inhibition in AML has so far failed to yield convincing responses.42
Another potential avenue for controlling AML with the immune system is by vaccination, though strong clinical data here are also currently lacking. Vaccination against WT1 with a leukemia-specific peptide combined with an adjuvant failed to show any demonstrable effect of clini- cal response in a small cohort of AML patients43 and another similarly designed trial was stopped after the first four patients failed to show any clinical response (clinical- trials.gov identifier: 00433745). An alternative form of vac- cination is a novel cell therapy involving the generation of autologous dendritic cell / AML fusion cells ex vivo which are then re-infused with the intention of expanding AML- reactive T cells in vivo. Safety and tolerability were
demonstrated in a small trial of AML patients who achieved remission after standard induction chemothera- py (patients who did not achieve a CR were excluded from the trial),44 and in a recent update, 12 of 17 vaccinat- ed patients (71%) remained in remission with a median follow up of 57 months.45 These findings suggest that vac- cination could be a useful consolidative therapy for patients achieving a CR, perhaps in those at high risk for relapse. This approach is currently being evaluated in a post-alloHSCT setting, both as single agent therapy and in combination with decitabine (clinicaltrials.gov identifier: 03679650). Overall, however, data that vaccination can directly mediate an anti-leukemia response in patients with active disease are lacking.
How will acute myeloid leukemia respond to chimeric antigen receptor T-cell therapy?
The potential for T-cell mediated killing of AML is manifest in the induction of long-term remissions in some patients after alloHSCT and donor lymphocyte infusions, suggesting AML can indeed be susceptible to T-cell medi- ated effects, and by extension, to CART therapy. However, alloHSCT fails to induce a sufficient graft-ver- sus-leukemia effect in some patients with AML having demonstrated numerous mechanisms of resistance to therapy over the years, including loss of HLA molecules in relapse post alloHSCT,46,47 upregulation of anti-apoptot- ic proteins, downregulation of antigen expression, and changes in T-cell populations, including T-cell exhaustion and the expansion of regulatory T cells.48 It remains to be seen what immune evasion mechanisms AML will gener- ate in response to CART therapy, though it is likely that many of the mechanisms of resistance to or relapse fol- lowing CART therapy in other diseases will also be seen in AML, such as relapse with antigen loss,49 generation of
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haematologica | 2019; 104(7)