Immune Responses and Long-Term Disease Recurrence Status After Telomerase-Based Dendritic Cell Immunotherapy in Patients with Acute Myeloid Leukemia

Results

Results

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Summary

In the current study, the authors evaluated the therapeutic potential of human telomerase reverse transcriptase (hTERT)-expressing autologous dendritic cells (hTERT-DCs) in patients with acute myeloid leukemia (AML). The hTERT-DCs were well tolerated with no severe toxicities reported and the generation of hTERT-DCs is feasible, the vaccination with hTERT-DCs also appears to be safe and may be associated with favorable recurrence-free survival.

Introduction

33 patients age 30 – 75 years old with the median age 58 years old with acute myeloid leukemia. Patients had a diagnosis of AML in CR1 with intermediate-risk or high-risk cytogenetics or in CR2 with a CR1 duration of >6 months.

Eastern Cooperative Oncology Group performance (ECOG) status had to be <1, and with adequate hepatic and renal function.

Methodology

Vaccine Preparation:
For DC culture, a concentrated leukocyte fraction was harvested by leukapheresis. PBMC were isolated from the leukapheresis product by density gradient centrifugation over polysucrose/sodium diatrizoate, and cells were resuspended in serum-free AIM-V medium. PBMC were incubated in a humidified incubator for 2 h at 37°C to allow plastic adherence. The semi adherent cell fraction was used for DC culture by incubation in serum-free X-VIVO 15 medium supplemented with recombinant human IL-4 (500 U/ml) and recombinant human GM- CSF (800 U/ml). After a 7-day culture period, cells were harvested and used for mRNA transfection. hTERT or LAMP hTERT mRNA was generated by in vitro transcription.

Transfection of immature DC with hTERT or LAMP hTERT mRNA was performed by electroporation. DC were washed twice in PBS, counted, and resuspended at a concentration of 4×107 cells/ml in ViaSpan. Cells were then coincubated for 5 min with 1 g of RNA per 1×106 cells on ice and electroporated in 0.4-cm cuvettes via exponential decay delivery at 300 V and 150 F. After electroporation, cells were centrifuged, resuspended in X- VIVO 15 medium, and matured for 20 hours in the presence of TNF- , IL-1 , IL-6, and PGE2.

Treatment

All 21 patients received 3 doses of hTERT-DCs. The median number of hTERT-DC vaccinations received by patients was 19 (range, 3-32 vaccinations). Twenty of the 21 patients (95%) received the full complement of 6 primary vaccinations and 13 patients (62%) received all 6 intended primary and boost vaccinations.

Results

Adverse Events
Of the 21 patients who received hTERT-DCs, 20 patients (95%) reported at least 1 AE after hTERT- DC treatment was initiated (treatment emergent), with 6 patients (29%) having at least 1 AE with a severity grade 3. The treatment- emergent AEs may or may not have been related to the hTERT-DCs. hTERT-DC-related AEs were reported in 9 of the 21 patients (43%). These included hTERT-DC vaccine site reactions, which were mild and consisted of grade 1 erythema and induration. During the hTERT-DC treatment period, a total of 6 patients (29%) who received hTERT-DCs experienced AEs of grade 3. Fatigue and headache, which each occurred in 24% of patients (5 of 21 patients), were the most common AEs reported. Of those AEs, 3 were SAEs affecting 2 patients (10%) who received hTERT-DCs. One patient experienced grade 4 idiopathic thrombocytopenic purpura, which resulted in hospitalization and platelet infusion and was considered possibly related to the hTERT-DC vaccine. This patient eventually developed disease recurrence with AML. The other patient with 2 SAEs experienced grade 3 perforated appendicitis and small intestinal obstruction that
resolved with surgery; the latter SAEs were considered to be unrelated to the hTERT-DC vaccine whereas the former was considered to be possibly related. There were no safety-related patient deaths reported during the study period.

hTERT Immune Responses
Eleven of the 19 patients (58%) receiving hTERT- DC vaccinations while in CR developed positive hTERT T-cell responses at 1 time points after the administration of the hTERT-DCs. Eight of 11 patients (73%) with hTERT-specific T cells had measurable T-cell responses at 2 additional time points after hTERT-DC vaccination.

Disease Recurrence
14 of 19 patients (74%) (median follow-up,18 months) who received hTERT-DCs during CR remained free of disease recurrence. Of the 14 patients who remained free of disease recurrence, 9 (64%) developed hTERT-specific T-cell responses during the vaccination period. Two of the 5 patients who developed disease recurrence (40%) had developed detectable hTERT-specific T- cell responses. Of the 3 patients who were in CR2 at the time of vaccination, all 3 remained in CR (median follow-up, 24 months). Two of the 3 patients in CR2 developed immune responses to hTERT. The study also included 7 patients aged >60 years, a group typically considered to be at high risk of disease recurrence. 5 of these 7 patients (71%) remained free of disease recurrence (median follow-up, 18 months), with all 5 patients developing T-cell immune responses to hTERT. After long-term follow-up, 11 of 19 patients who received hTERT-DCs in CR were free of disease recurrence (median follow-up, 52 months) at the time of last follow-up. Of the 3 patients who received hTERT-DCs in CR2, 2 were still free of disease recurrence at 50 months and 59 months, respectively, after the initiation of vaccination, whereas the third patient was lost to follow-up at 2 years. Both of the recurrence-free patients in CR2 developed specific T-cell immune responses to telomerase.

Conclusion

The generation of hTERT-DCs is feasible and vaccination with hTERT-DCs appears to be safe and may be associated with favorable recurrence-free survival.

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Scientific article publishing date : 14/4/2017

Immucura identifier : BSC21_049EN

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