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CTRI Number  CTRI/2021/09/036713 [Registered on: 21/09/2021] Trial Registered Prospectively
Last Modified On: 10/09/2021
Post Graduate Thesis  No 
Type of Trial  Interventional 
Type of Study   Drug 
Study Design  Single Arm Study 
Public Title of Study   Abatacept Mediated Natural Killer Cell-Based Immunotherapy  
Scientific Title of Study   "Natural Killer (NK) Cell-based Immunotherapy for Acute Leukemia with Abatacept (CTLA4-Ig): Exploring the Crosstalk between NK cells and Monocyte/ Macrophages." 
Trial Acronym  Abatacept mediated NK cell Immunotherapy (ABANI) 
Secondary IDs if Any  
Secondary ID  Identifier 
NIL  NIL 
 
Details of Principal Investigator or overall Trial Coordinator (multi-center study)  
Name  Sarita Rani Jaiswal  
Designation  Program Director, Blood and Marrow Transplantation  
Affiliation  Dharmshila Narayana Superspecial 
Address  Dept of BMT and Hematology, 4th Floor, A Block, Vasundhra Enclave

East
DELHI
110096
India 
Phone  9874292709  
Fax    
Email  drsaritaranij@gmail.com  
 
Details of Contact Person
Scientific Query  
Name  Suparno Chakrabarti  
Designation  Director 
Affiliation  Manashi Chakrabarti Foundation 
Address  Cellular Therapy and Immunology, Tower-2, Flat-702 UPOHAR HIG Complex, Kolkata

Kolkata
WEST BENGAL
7000094
India 
Phone  9871127809  
Fax    
Email  foundationforcure@gmail.com  
 
Details of Contact Person
Public Query  
Name  Suparno Chakrabarti  
Designation  Director 
Affiliation  Manashi Chakrabarti Foundation 
Address  Cellular Therapy and Immunology, Tower-2, Flat-702 UPOHAR HIG Complex, Kolkata

Kolkata
WEST BENGAL
7000094
India 
Phone  9871127809  
Fax    
Email  foundationforcure@gmail.com  
 
Source of Monetary or Material Support  
Manashi Chakrabarti Foundation 
 
Primary Sponsor  
Name  Manashi Chakrabarti Foundation 
Address  32 PGH Shah Road, Jadavpur, WB 
Type of Sponsor  Research institution 
 
Details of Secondary Sponsor  
Name  Address 
NIL  NIL 
 
Countries of Recruitment     India  
Sites of Study  
No of Sites = 1  
Name of Principal Investigator  Name of Site  Site Address  Phone/Fax/Email 
Sarita Rani Jaiswal  Dharmshila Narayana Superspeciality hosiptal   Dept of BMT and Hematology, Dharmshila Narayana Superspeciality hosiptal, Vasundhra Enclave, New Delhi
East
DELHI 		 9874292709

drsaritaranij@gmail.com 
 
Details of Ethics Committee  
No of Ethics Committees= 1  
Name of Committee  Approval Status 
Ethics Committee-DNSH  Approved 
 
Regulatory Clearance Status from DCGI  
Status 
Not Applicable 
 
Health Condition / Problems Studied  
Health Type  Condition 
Patients  (1) ICD-10 Condition: D759||Disease of blood and blood-formingorgans, unspecified,  
 
Intervention / Comparator Agent  
Type  Name  Details 
Intervention  Abatacept and Donor Lymphocyte Infusion  1) Abatacept as T cell COSBL at 10 mg/kg/dose shall be used on Days-1, +7,+21, +35 in malignant diseases. 2) DLI- Patients shall receive donor lymphocyte infusions as per established protocol on days +7, +21 and +35, 6 hours after the infusion of CTLA4Ig. The intervention is currently the standard of care in allogenic bone marrow transplantation in our institution following successful clinical trials in the past. The current study aims to explore the mechanistic pathway of the favourable impact of this intervention on NK cells post BMT. 
Comparator Agent  NIL  NIL 
 
Inclusion Criteria  
Age From  2.00 Year(s)
Age To  65.00 Year(s)
Gender  Both 
Details  · First allogeneic transplant.
· Age between 2 and 65 years.
· Patients must have a related donor that is HLA-matched at least 5 of 10 HLA A, B, C, DRB1, DQB.
· Cardiac function: Shortening fraction >25%; ejection fraction >40%
· Estimated creatinine clearance greater than 50 mL/minute
· Pulmonary function: DLCO ≥40% (adjusted for hemoglobin) and FEV1≥70%, oxygen saturation>91%
· Liver function: direct (conjugated) bilirubin < 2x the upper limit of normal and ALT/AST < 2.5x the upper normal limit
· No major organ disfunction
· Signed informed consent 
 
ExclusionCriteria 
Details  · Life expectancy less than 6 months
· Patients with uncontrolled bacterial, viral or fungal infections (undergoing appropriate treatment and with progression of clinical symptoms) within 1 month prior to conditioning. Patients with febrile illness or suspected minor infection should await clinical resolution prior to starting conditioning.
· Pregnant or breastfeeding patients
· Patients seropositive for the human immunodeficiency virus (HIV)
· Patient with active Hepatitis B or C determined by serology and/or NAAT not on treatment
· Active hepatitis, bridging fibrosis or cirrhosis on liver biopsy (biopsy required for patients on chronic transfusion therapy for > 1 year and evidence of iron overload with ferritin >1000 ng/mL)
· Patients with suitable 10/10 HLA matched related and unrelated donors
 
 
Method of Generating Random Sequence   Not Applicable 
Method of Concealment   Not Applicable 
Blinding/Masking   Not Applicable 
Primary Outcome  
Outcome  TimePoints 
The potential of CTLA4Ig in sparing and/or potentiating NK cell cytotoxicity is an unexplored and yet an exciting possibility in the field of cellular therapy with initial clinical data strongly suggesting a favourable impact of the molecule on NK cell function. This study will help in establishment of the mechanistic pathway underlying this phenomenon.
The exploration of the crosstalk between NK cells and monocyte/macrophages might uncover hitherto unknown pathways by which anti-leukemia activity of NK cells is potentiated.
 		 24 months 
 
Secondary Outcome  
Outcome  TimePoints 
The translational impact of unraveling the interaction between NK cells and monocyte/macrophages on exposure to CTLA4Ig might have a far-reaching impact in the field of cellular therapy, wherein a unique and more importantly, an affordable scalable platform for NK cell-based immunotherapy could be established, both in the context of HCT and without HCT.  24 months 
 
Target Sample Size   Total Sample Size="20"
Sample Size from India="20" 
Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials"
Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials" 
Phase of Trial   Phase 2 
Date of First Enrollment (India)   01/10/2021 
Date of Study Completion (India) Applicable only for Completed/Terminated trials 
Date of First Enrollment (Global)  Date Missing 
Date of Study Completion (Global) Applicable only for Completed/Terminated trials 
Estimated Duration of Trial   Years="2"
Months="0"
Days="0" 
Recruitment Status of Trial (Global)   Not Applicable 
Recruitment Status of Trial (India)  Not Yet Recruiting 
Publication Details   none from the current trial 
Individual Participant Data (IPD) Sharing Statement

Will individual participant data (IPD) be shared publicly (including data dictionaries)?  

Response - YES
  1. What data in particular will be shared?
    Response - Individual participant data that underlie the results reported in this article, after de-identification (text, tables, figures, and appendices).

  2. What additional supporting information will be shared?
    Response -  Study Protocol
    Response - Informed Consent Form
    Response - Clinical Study Report

  3. Who will be able to view these files?
    Response - Researchers whose proposed use of the data has been approved by an independent review committee identified for this purpose.

  4. For what types of analyses will this data be available?
    Response - For individual participant data meta-analysis.

  5. By what mechanism will data be made available?
    Response - Proposals should be directed to [drsaritaranij@gmail.com].

  6. For how long will this data be available start date provided 01-09-2023 and end date provided 01-09-2026?
    Response - Beginning 9 months and ending 36 months following article publication.

  7. Any URL or additional information regarding plan/policy for sharing IPD? 
    Additional Information - NIL
Brief Summary  
  • Hematopoietic Cell Transplantation (HCT) remains the only curative option for majority of the patients with acute leukemia. However, disease progression (DP) remains the major cause for treatment failure in these patients. The advent of post-transplantation cyclophosphamide (PTCy) has resulted in an explosion of HCT from a Haploidentical family donor (HFD) over the last few years. Yet, the incidence of relapse after PTCy-based HFD-HCT has remained extremely high. Innovative and yet affordable cellular therapies, which would provide a potent anti-leukemia effect without increase in toxicity are an unmet need. 
  • Since its first use in late 1980, donor lymphocyte infusions (DLI) has been the only proven approach for treatment as well as prevention of DP after HCT. However, the use of DLI has been largely restricted to the treatment of overt or impending relapse, due to concerns regarding graft-versus-host disease (GVHD) mediated by T cells. On the other hand, the major non-T cell lymphocytes, the natural killer (NK) cells have shown to have strong anti-leukemia effect. 
  • In the context of allogeneic HCT, NK cells are the first lymphoid population to recover. However, the recovering NK cells belong to an immature phenotype with high expression of CD56 and inhibitory receptors. With maturation i.e. acquisition of CD56dim phenotype, the NK cells loose NKG2A expression as these cells are now ‘licensed’. It has been shown repeatedly that immature NK cells fail to exert cytotoxicity and might in-fact increase the risk of GVHD following an allogeneic HCT.
  •  Abatacept (CTLA4Ig) is a fusion construct of CTLA4 and Fc region of human IgG, which blocks T cell activation by avidly binding to CD80/86 and thus preventing the ligation of CD28. Animal studies had established the fact that NK cells were inherently resistant of to CTLA4Ig. We conjectured that CTLA4Ig if given before DLI might prevent T cell mediated GVHD and yet allow NK cell mediated anti-leukemia effect. 
  • We explored the efficacy of prophylactic DLI following CTLA4Ig (CTLA4Ig-DLI group, n=75), compared to conventional DLI (DLI group, n=50), in patients with advanced hematological malignancies receiving PTCy-based haploidentical transplantation. CTLA4Ig-DLI group had reduced incidence of GVHD as well as DP, with a superior recovery of mature NK cells. The next question that arose was if CTLA4Ig merely spared the NK cells or it augmented NK cell mediated cytotoxicity in any way. 
  • The mechanism through which CTLA4Ig influences proliferation and cytotoxicity of NK cells has not been elucidated. CTLA4Ig ligates with CD80 and CD86 ligands on monocyte/macrophages and dendritic cells. Macrophage polarisation has been shown to influence NK cell functions. The current study aims to explore the mechanistic pathway of crosstalk between NK cells and monocyte/macrophages in the presence of CTLA4Ig. Elucidation of this pathway might provide a unique platform for adoptive cellular therapy for acute leukemia.

 
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