Neoplasms

Blood and Lymph Conditions

All Conditions

Leukemia

Patient to receive pooled granulocytes for 7 days concurrently. 10 participants will be approached for this arm.

Non-randomised control arm, where patients who are receiving a stem cell transplant, as described in the eligibility criteria, are asked for a blood sample. This is to establish a baseline versus the experimental arm. 10 participants will be approached for this arm.

Receive granulocytes for 7 consecutive days after engraftment post transplant

Granulocytes

Robert Wynn, MD FRCPath

Roisin Borrill, MRCPCH

Although most children with leukaemia are cured using drugs (chemotherapy) alone, for some children additional treatments are needed. Stem cell transplant can cure children where chemotherapy and other drugs have failed. In this case, the immune cells of the donor attack the leukaemia cells of the patient. Cord blood collected from the placenta of unrelated babies is often used as a donor cell source and appears to work well at controlling leukaemia and less likely to cause complications such as when the immune cells also mistakenly attack healthy tissues (called graft versus host disease, GVHD).

The investigators have noticed that during cord blood transplant, the donor immune system appears to recover more quickly and not be associated with GVHD, when a type of blood transfusion containing white cells are also given to the patient. The infused white cells appear to stimulate the donor immune cells to expand much more than usually seen.

During this research, the investigators will study this immune cell expansion during cord blood transplant in children with difficult-to-cure leukaemia who also receive a transfusion of white cells, termed granulocytes. The investigators will assess the safety of the effects of the white cell transfusions and the immune cell expansion on the child, and look at the outcomes on the patient's leukaemia, and whether there is GVHD or not.

Most children with acute leukaemia are cured with chemotherapy alone but a few children are either refractory to such therapy, or relapse after it has been administered.

Some of these relapsed or refractory children are given HCT (hematopoietic cell transplantation), and some will be cured with HCT. HCT acts to cure children with leukaemia in two ways:

* There is chemotherapy given before the transplant, to get rid of recipient marrow and the recipient immune system. This chemotherapy is of higher dose than is given in standard chemotherapy protocols, and this dose escalation might overcome the resistance to chemotherapy that is inherent in children with relapsed or refractory disease.
* The engrafting immune system - derived from the HCT donor - recognises the residual leukaemia and rejects it. This is known as graft-versus-leukaemia, and this Is the main way that transplant cures refractory diseases.

Most children with refractory and / or relapsed leukaemia will die of their leukaemia. Transplant offers a chance of cure where conventional therapies will fail. Transplant works through this graft-versus leukaemia effect. This is related to graft-versus-disease (GVHD) and involves a recognition by donor derived T-cells of differences in the host leukaemia cells, and more generally in the recipient.

In general, the risk of relapse after transplant is:

* Reduced where there is graft versus host disease
* Reduced where the T-cells are left in the graft, a T-cell replete transplant. Often T-cells are removed from the graft - bone marrow, blood, or cord blood - to reduce the risk of GVHD
* Reduced where there is mismatch between the donor and recipient. The investigators and others have shown that it is possible to do T-cell replete, mismatched unrelated donor transplant in umbilical cord transplant.
* The risk of relapse is less in cord blood transplant compared to other cell sources, and this is particularly evident where there is residual disease present, and the risk of treatment failure is highest.
* The risk of chronic GVHD is reduced after cord blood transplant, even where the transplant is T-cell replete and there is mismatch between donor and recipient. Using adult donor-derived, mismatched donor transplant in a T-cell replete setting is associated with a risk of severe acute GVHD and chronic, extensive GVHD which limits quality of life.
* The most meaningful endpoint for children undergoing transplantation for any indication is disease-free and chronic GVHD-free survival. In malignancy this is best achieved using cord blood in a T-cell replete setting.

One of the investigators groups have published data from a xenograft model demonstrating that cord blood T-cells are better at controlling a human leukaemia than adult T-cells, and that the actual cord T-cells infiltrating the xenografted tumour are Cluster of Differentiation 810 (CD810). However, after T-cell replete transplant most of the recovering T-cells are Cluster of Differentiation 4 (CD4) and not Cluster of Differentiation (CD812). Childhood leukaemia is a rapidly proliferative disease, and experience tells us that relapse can happen early, within the first weeks and months. A graft versus tumour effect must be established quickly therefore, to prevent disease recurrence, and death from disease.

In this research, the investigators seek to replicate results that have been described and published prior. Here the investigators demonstrated early, transient, massive Cluster of Differentiation (CD8) T-cell reconstitution after cord blood transplantation without any chronic GVHD, despite early cessation of post-transplant immune suppression.

This observation is important since it incorporates the important components of a clinically meaningful graft-versus-leukaemia, from previous work:

* CD8 biased
* Cord blood
* T-cell replete setting
* Mismatched donors
* No chronic GVHD

This has been recognized by leaders in the field, and as part of the peer review of this work. Milano, an expert in Cord Blood transplant in refractory leukaemia has written that "this is not only economically beneficial but may also result in a paradigm shift for the treatment of patients with high-risk leukaemia's. "

The trial is funded by bone marrow transplant local funds and by funds generated specifically for this research by families, including families with difficult-to-cure, including multiple relapsed and refractory leukaemia. The rationale and patient summaries have been shared with those families, in support of their fundraising efforts. Families of children with such leukaemia understand how transplant works, the risk it generates and the implications when cell therapies also fail where conventional therapy has already failed. They are the best placed of all of us to understand this balance of risk of therapy with risk of treatment failure, and the best placed therefore to understand the rationale and scope of this research.

It is important to replicate the data that the investigators have published. It is important that in a trial setting that the investigators better define the safety of the immune cell expansion, and the nature of the T-cells that are derived. It is important research, for the reasons explained above, and recognised by Milano and other commentators.

There is a control group for T-cell expansion numbers, and for safety evaluations including cytokine release syndrome and engraftment kinetics. This is not an efficacy trial, and the relapsed, refractory leukaemia is rare in children, and so randomisation is not appropriate. The granulocyte doses are standard for children, and what the investigators reported in their preliminary experience.

Granulocyte Transfusions After Umbilical Cord Blood Transplant

The Use of Granulocyte Transfusions After Umbilical Cord Blood Transplant for Leukaemia: A Prospective, Non-randomised, Single-centre Study to Evaluate Safety and Immune Reconstitution

This is to access safety of the granulocyte infusions.

This is to measure the effect that the granulocyte infusion course have on engraftment and on the disease

Children's Cancer and Leukaemia Group

University of Manchester

Fresh, non-irradiated granulocytes from ABO, Rh, CMV compatible, unrelated donors; bioactivity of anti-cancer ability meets the criteria.

Granulocytes cross-matched for ABO-Rh and CMV; bioactivity of anti-cancer ability meets the criteria.

Wenjun Le, Ph.D

Zhongming Liu, MD/Ph.D

Yifan Zhang

Background \& Rationale:

For years, most tumor immunotherapy researches have focused on T cell and natural killer (NK) cell therapies, most of which involve amplification and modification of the patient's immune cells for reinfusion therapy. However, for the treatment of solid tumors, there is currently little breakthrough. Recently, researchers have reported a colony of cancer-resistant mice developed from a single mouse that was immune to multiple lethal cancer cell injections. Further research revealed that such anti-cancer immunity can cause rapid shrinkage or disappearance of the tumors in other cancer-bearing mice. Interestingly, this therapeutic effect is due to the donor granulocytes, instead of T cells or NK cells. Infusion of granulocytes is a classic therapy in treating infection associated with granulocytopenia. Currently, clinical collection of blood components, including isolation of granulocytes, is a mature technique. The infusion of granulocytes is a viable anticancer therapy combining the classic technique and novel anticancer approach. This proposed trial will test whether granulocyte infusions from healthy unrelated donors can be used to treat advanced cancer. In the proposed trial, up to 100 Subjects with advanced cancer can be entered. Each patient will be given a dose of (2.0-5.0)x10\^10 granulocytes from a different healthy donor every week over a course of 5 doses. The trial will evaluate the subject's cancer 7, 30, 90 and 180 days after the last infusion.

Granulocyte anti-cancer therapy refers to a method in which healthy donor granulocytes with high cancer-killing activity are collected and infused into a specific cancer patient by matching, to achieve the therapeutic anticancer effect. In this proposed trial, up to 100 Subjects with advanced cancer can be entered. Potentially hundreds of healthy Donor-participants will be recruited. First, granulocyte donors will be identified via in-vitro assay of Cancer Killing Activity (CKA), which screens healthy Donor-participants for those with anticancer activity of more than 80%. Secondly, after donor-recipient blood matching, (2.0-5.0)x10\^10 granulocytes will be collected from each donor, accounting for about 1/10 of the human body. Each patient will be given a dose of (2.0-5.0)x10\^10 granulocytes from a different donor per week over a course of 5 doses (with an ideal total infusion of 2X10\^11 granulocytes). After each infusion, the patients will be monitored carefully for possible adverse events. If adverse events occur, the infusion can be slowed down or stopped until the adverse events can be managed. The trial will observe the subject's cancer 7, 30, 90 and 180 days after the last infusion. Target lesions, non-target lesions, and new lesions will be evaluated via medical imaging and tumor markers. The responses will be compared against the measurements at baseline.

Clinical Study of Granulocyte Infusion for Advanced Cancer

Clinical Study of Allogeneic Granulocyte Infusion in the Treatment of Patients With Advanced Cancer

The trial will observe the subject's progression free survival for 3 months after the granulocyte infusions are completed.

The patients will be followed 1 week, 1 month, 3 months and 6 months after the last treatment. Median Overall Survival will be measured as the length of time from the date of inclusion that half of the patients are still alive.

Objective Response Rate will be evaluated based on the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1. If a response is achieved in a patient, the evaluation will be repeated 4-6 weeks after the first evaluation to confirm the response.

Disease Control Rate will be measured as the percentage of patients achieved complete response (CR), partial response (PR) and stable disease (SD) to the treatment (evaluated based on RECIST 1.1).

ECOG Scale of Performance Status will be evaluated for patients after treatment to reflect impact on quality of life.

Incidence of treatment-related adverse events as assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Granulocyte Transfusions After Umbilical Cord Blood Transplant	NCT05425043	Pediatric Cance...	Granulocytes	- 16 Years	University of Manchester
Granulocyte Transfusions After Umbilical Cord Blood Transplant	NCT05425043	Pediatric Cance...	Granulocytes	- 16 Years	University of Manchester
Clinical Study of Granulocyte Infusion for Advanced Cancer	NCT04124666	Advanced Cancer	Granulocytes	18 Years -	Shanghai East Hospital
Granulocyte Transfusions After Umbilical Cord Blood Transplant	NCT05425043	Pediatric Cance...	Granulocytes	- 16 Years	University of Manchester

Spots Global Cancer Trial Database for granulocytes

Every month we try and update this database with for granulocytes cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.