EHA Library - The official digital education library of European Hematology Association (EHA)

REPEATED INFUSIONS OF ESCALATING DOSES OF EXPANDED AND ACTIVATED AUTOLOGOUS NATURAL KILLER CELLS IN MINIMAL RESIDUAL DISEASE-POSITIVE PH+ ACUTE LYMPHOBLASTIC LEUKEMIA PATIENTS. A GIMEMA PHASE 1 TRIAL
Author(s): ,
Giovanni Fernando Torelli
Affiliations:
Hematology, Department of Translational and Precision Medicine,Sapienza University,Rome,Italie;Hematology, Department of Translational and Precision Medicine,Sapienza University,Rome,Italien;Hematology, Department of Translational and Precision Medicine,Sapienza University,Rome,Italia;Hematology, Department of Translational and Precision Medicine,Sapienza University,Rome,Italy;Hematology, Departme
,
Sabina Chiaretti
Affiliations:
Hematology, Department of Translational and Precision Medicine,Sapienza University ,Rome,Italie;Hematology, Department of Translational and Precision Medicine,Sapienza University ,Rome,Italien;Hematology, Department of Translational and Precision Medicine,Sapienza University ,Rome,Italia;Hematology, Department of Translational and Precision Medicine,Sapienza University ,Rome,Italy;Hematology, Depa
,
Nadia Peragine
Affiliations:
Hematology, Department of Translational and Precision Medicine,Sapienza University,Rome,Italie;Hematology, Department of Translational and Precision Medicine,Sapienza University,Rome,Italien;Hematology, Department of Translational and Precision Medicine,Sapienza University,Rome,Italia;Hematology, Department of Translational and Precision Medicine,Sapienza University,Rome,Italy;Hematology, Departme
,
Walter Barberi
Affiliations:
Hematology, Department of Translational and Precision Medicine,Sapienza University,Rome,Italie;Hematology, Department of Translational and Precision Medicine,Sapienza University,Rome,Italien;Hematology, Department of Translational and Precision Medicine,Sapienza University,Rome,Italia;Hematology, Department of Translational and Precision Medicine,Sapienza University,Rome,Italy;Hematology, Departme
,
Laura Santodonato
Affiliations:
FaBioCell Cell Factory,Istituto Superiore di Sanità,Rome,Italie;FaBioCell Cell Factory,Istituto Superiore di Sanità,Rome,Italien;FaBioCell Cell Factory,Istituto Superiore di Sanità,Rome,Italia;FaBioCell Cell Factory,Istituto Superiore di Sanità,Rome,Italy;FaBioCell Cell Factory,Istituto Superiore di Sanità,Rome,Italia;FaBioCell Cell Factory,Istituto Superiore di Sanità,Rome,Italië;FaBioCell Cell F
,
Giuseppina D'Agostino
Affiliations:
FaBioCell Cell Factory,Istituto Superiore di Sanità,Rome,Italie;FaBioCell Cell Factory,Istituto Superiore di Sanità,Rome,Italien;FaBioCell Cell Factory,Istituto Superiore di Sanità,Rome,Italia;FaBioCell Cell Factory,Istituto Superiore di Sanità,Rome,Italy;FaBioCell Cell Factory,Istituto Superiore di Sanità,Rome,Italia;FaBioCell Cell Factory,Istituto Superiore di Sanità,Rome,Italië;FaBioCell Cell F
,
Elisabetta Abruzzese
Affiliations:
Hematology,Sant'Eugenio Hospital, ASL Roma2, Tor Vergata University,Rome,Italie;Hematology,Sant'Eugenio Hospital, ASL Roma2, Tor Vergata University,Rome,Italien;Hematology,Sant'Eugenio Hospital, ASL Roma2, Tor Vergata University,Rome,Italia;Hematology,Sant'Eugenio Hospital, ASL Roma2, Tor Vergata University,Rome,Italy;Hematology,Sant'Eugenio Hospital, ASL Roma2, Tor Vergata University,Rome,Italia;
,
Maria Ilaria Del Principe
Affiliations:
Hematology, Department of Biomedicine and Prevention,Tor Vergata University,Rome,Italie;Hematology, Department of Biomedicine and Prevention,Tor Vergata University,Rome,Italien;Hematology, Department of Biomedicine and Prevention,Tor Vergata University,Rome,Italia;Hematology, Department of Biomedicine and Prevention,Tor Vergata University,Rome,Italy;Hematology, Department of Biomedicine and Preven
,
Alessandra Mancino
Affiliations:
Fondazione GIMEMA Onlus,Rome,Italie;Fondazione GIMEMA Onlus,Rome,Italien;Fondazione GIMEMA Onlus,Rome,Italia;Fondazione GIMEMA Onlus,Rome,Italy;Fondazione GIMEMA Onlus,Rome,Italia;Fondazione GIMEMA Onlus,Rome,Italië;Fondazione GIMEMA Onlus,Rome,Itália;Fondazione GIMEMA Onlus,Rome,Италия;Fondazione GIMEMA Onlus,Rome,Italien
,
Mabel Matarazzo
Affiliations:
Hematology, Department of Translational and Precision Medicine,Sapienza University,Rome,Italie;Hematology, Department of Translational and Precision Medicine,Sapienza University,Rome,Italien;Hematology, Department of Translational and Precision Medicine,Sapienza University,Rome,Italia;Hematology, Department of Translational and Precision Medicine,Sapienza University,Rome,Italy;Hematology, Departme
,
Mahnaz Shafii Bafti
Affiliations:
Hematology, Department of Translational and Precision Medicine,Sapienza University,Rome,Italie;Hematology, Department of Translational and Precision Medicine,Sapienza University,Rome,Italien;Hematology, Department of Translational and Precision Medicine,Sapienza University,Rome,Italia;Hematology, Department of Translational and Precision Medicine,Sapienza University,Rome,Italy;Hematology, Departme
,
Marco Mancini
Affiliations:
Hematology, Department of Translational and Precision Medicine,Sapienza University,Rome,Italie;Hematology, Department of Translational and Precision Medicine,Sapienza University,Rome,Italien;Hematology, Department of Translational and Precision Medicine,Sapienza University,Rome,Italia;Hematology, Department of Translational and Precision Medicine,Sapienza University,Rome,Italy;Hematology, Departme
,
Monica Messina
Affiliations:
Fondazione GIMEMA Onlus,Rome,Italie;Fondazione GIMEMA Onlus,Rome,Italien;Fondazione GIMEMA Onlus,Rome,Italia;Fondazione GIMEMA Onlus,Rome,Italy;Fondazione GIMEMA Onlus,Rome,Italia;Fondazione GIMEMA Onlus,Rome,Italië;Fondazione GIMEMA Onlus,Rome,Itália;Fondazione GIMEMA Onlus,Rome,Италия;Fondazione GIMEMA Onlus,Rome,Italien
,
Luciano Castiello
Affiliations:
FaBioCell Cell Factory,Istituto Superiore di Sanità,Rome,Italie;FaBioCell Cell Factory,Istituto Superiore di Sanità,Rome,Italien;FaBioCell Cell Factory,Istituto Superiore di Sanità,Rome,Italia;FaBioCell Cell Factory,Istituto Superiore di Sanità,Rome,Italy;FaBioCell Cell Factory,Istituto Superiore di Sanità,Rome,Italia;FaBioCell Cell Factory,Istituto Superiore di Sanità,Rome,Italië;FaBioCell Cell F
,
Anna Guarini
Affiliations:
Hematology, Department of Translational and Precision Medicine,Sapienza University,Rome,Italie;Hematology, Department of Translational and Precision Medicine,Sapienza University,Rome,Italien;Hematology, Department of Translational and Precision Medicine,Sapienza University,Rome,Italia;Hematology, Department of Translational and Precision Medicine,Sapienza University,Rome,Italy;Hematology, Departme
Robin Foà
Affiliations:
Hematology, Department of Translational and Precision Medicine,Sapienza University,Rome,Italie;Hematology, Department of Translational and Precision Medicine,Sapienza University,Rome,Italien;Hematology, Department of Translational and Precision Medicine,Sapienza University,Rome,Italia;Hematology, Department of Translational and Precision Medicine,Sapienza University,Rome,Italy;Hematology, Departme
(Abstract release date: 05/12/22) EHA Library. Fernando Torelli G. 06/12/22; 356976; S111
Giovanni Fernando Torelli
Giovanni Fernando Torelli
Contributions
Abstract
Presentation during EHA2022: All Oral presentations will be presented between Friday, June 10 and Sunday, June 12 and will be accessible for on-demand viewing from Monday, June 20 until Monday, August 15, 2022 on the Congress platform.

Abstract: S111

Type: Oral Presentation

Session title: Novel insights into the treatment of ALL

Background

Due to age and co-morbidities, many Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) patients are ineligible to undergo high-dose chemotherapy or allogeneic transplant as consolidation treatment. Our group reported the promising results of the chemo-free scheme D-ALBA based on dasatinib/blinatumomab in induction/consolidation, underlying the potential role of immunotherapy in this setting (Foà et al, NEJM 2020;383:1616-23).

Considerable interest has been raised by natural killer (NK) cells. We developed a GMP protocol for NK cell ex vivo expansion in the presence of IL-2 and IL-15, and report the results of a phase 1 protocol of adoptive immunotherapy with activated and expanded autologous NK cells for Ph+ ALL patients in complete hematologic remission (CHR) but with persistent/recurrent minimal residual disease (MRD) ≥60 years or ineligible for other post-CHR treatment modalities.

Aims
The primary endpoint was to determine the maximum tolerated dose of NK cells and the recommended dose for subsequent studies. Secondary endpoints were the assessment of safety and tolerability of the treatment, the immunologic modifications induced by the procedure and the clinical response to treatment.

Methods

The planned 6 patients were enrolled: 5 in 1st CHR and 1 in 2nd CHR. Patients underwent repeated infusions (maximum 5) of escalating doses of NK cells, ranging from 1x106 to 5x107/kg of body weight (BW). No conditioning therapies were administered before the infusion; patients were allowed to continue tyrosine kinase inhibitors. Patients underwent a comprehensive MRD monitoring by Q-RT-PCR with a one-year follow-up. Immunophenotypic analysis on the NK cell product was performed before and after the expansion. Intracellular cytokine production and PBMC cytotoxic activity against K562 cells, allogeneic and autologous blasts were evaluated after expansion and at time 0 and 7 days from each NK cell infusion.

Results

NK cells presented a 12.3-fold ex vivo expansion. Expanded cells showed an increased expression of activating receptors and measurable cytotoxicity against primary allogeneic and autologous blasts. One patient received a maximum NK cell dose of 5x106 cells/kg, 2 patients 1x107 cells/kg and 3 5x107 cells/kg/BW. No patient experienced infusion-related toxicities. Two adverse events were recorded (grade 1 and 2), both judged not treatment-related, that resolved after TKI suspension. The higher cell dose infusion resulted in a significantly increased expression of natural cytotoxicity receptors, a greater cytokine production by NK, T and NKT cells, and in an increased capacity of PBMC to lyse K562 cells. These modifications appear persistent over time.

At a 1-year follow-up from the last infusion, 5/6 patients are alive in CHR (Table 1). The MRD levels reduced over time and 4/6 patients reached a complete molecular response (CMR) or a positive-not-quantifiable (PNQ) status during the study period. At a median follow-up of 30.8 months from the last infusion, the 5 patients who received the NK treatment in 1st CHR are still in CMR or PNQ, though 1 patient required additional treatment. The patient in 2nd CHR at the time of the infusions showed a rise in MRD and died of disease progression.

Conclusion

This phase 1 study demonstrates that autologous NK cells can be efficiently expanded ex vivo from MRD-positive Ph+ ALL patients in CHR. The infusion of these expanded cells is safe and induces a marked in vivo host immune response, suggesting that this approach represents a tolerable and feasible model worthy of being investigated in larger clinical studies.

Keyword(s): Cellular therapy, Minimal residual disease (MRD), Natural killer, Ph+ ALL

Presentation during EHA2022: All Oral presentations will be presented between Friday, June 10 and Sunday, June 12 and will be accessible for on-demand viewing from Monday, June 20 until Monday, August 15, 2022 on the Congress platform.

Abstract: S111

Type: Oral Presentation

Session title: Novel insights into the treatment of ALL

Background

Due to age and co-morbidities, many Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) patients are ineligible to undergo high-dose chemotherapy or allogeneic transplant as consolidation treatment. Our group reported the promising results of the chemo-free scheme D-ALBA based on dasatinib/blinatumomab in induction/consolidation, underlying the potential role of immunotherapy in this setting (Foà et al, NEJM 2020;383:1616-23).

Considerable interest has been raised by natural killer (NK) cells. We developed a GMP protocol for NK cell ex vivo expansion in the presence of IL-2 and IL-15, and report the results of a phase 1 protocol of adoptive immunotherapy with activated and expanded autologous NK cells for Ph+ ALL patients in complete hematologic remission (CHR) but with persistent/recurrent minimal residual disease (MRD) ≥60 years or ineligible for other post-CHR treatment modalities.

Aims
The primary endpoint was to determine the maximum tolerated dose of NK cells and the recommended dose for subsequent studies. Secondary endpoints were the assessment of safety and tolerability of the treatment, the immunologic modifications induced by the procedure and the clinical response to treatment.

Methods

The planned 6 patients were enrolled: 5 in 1st CHR and 1 in 2nd CHR. Patients underwent repeated infusions (maximum 5) of escalating doses of NK cells, ranging from 1x106 to 5x107/kg of body weight (BW). No conditioning therapies were administered before the infusion; patients were allowed to continue tyrosine kinase inhibitors. Patients underwent a comprehensive MRD monitoring by Q-RT-PCR with a one-year follow-up. Immunophenotypic analysis on the NK cell product was performed before and after the expansion. Intracellular cytokine production and PBMC cytotoxic activity against K562 cells, allogeneic and autologous blasts were evaluated after expansion and at time 0 and 7 days from each NK cell infusion.

Results

NK cells presented a 12.3-fold ex vivo expansion. Expanded cells showed an increased expression of activating receptors and measurable cytotoxicity against primary allogeneic and autologous blasts. One patient received a maximum NK cell dose of 5x106 cells/kg, 2 patients 1x107 cells/kg and 3 5x107 cells/kg/BW. No patient experienced infusion-related toxicities. Two adverse events were recorded (grade 1 and 2), both judged not treatment-related, that resolved after TKI suspension. The higher cell dose infusion resulted in a significantly increased expression of natural cytotoxicity receptors, a greater cytokine production by NK, T and NKT cells, and in an increased capacity of PBMC to lyse K562 cells. These modifications appear persistent over time.

At a 1-year follow-up from the last infusion, 5/6 patients are alive in CHR (Table 1). The MRD levels reduced over time and 4/6 patients reached a complete molecular response (CMR) or a positive-not-quantifiable (PNQ) status during the study period. At a median follow-up of 30.8 months from the last infusion, the 5 patients who received the NK treatment in 1st CHR are still in CMR or PNQ, though 1 patient required additional treatment. The patient in 2nd CHR at the time of the infusions showed a rise in MRD and died of disease progression.

Conclusion

This phase 1 study demonstrates that autologous NK cells can be efficiently expanded ex vivo from MRD-positive Ph+ ALL patients in CHR. The infusion of these expanded cells is safe and induces a marked in vivo host immune response, suggesting that this approach represents a tolerable and feasible model worthy of being investigated in larger clinical studies.

Keyword(s): Cellular therapy, Minimal residual disease (MRD), Natural killer, Ph+ ALL

By clicking “Accept Terms & all Cookies” or by continuing to browse, you agree to the storing of third-party cookies on your device to enhance your user experience and agree to the user terms and conditions of this learning management system (LMS).

Cookie Settings
Accept Terms & all Cookies