Immunotherapy Research at Great Ormond Street Hospital

We have awarded funding of £1,108,039. to Great Ormond Street Hospital for four projects looking at alternatives to conventional chemotherapy.

The aim of this type of work is not only to avoid some of the toxicity associated with current chemotherapy and radiotherapy regimes, but also to offer hope to the 20% of children who are still being failed by current treatments.

The body’s own immune system can play an important role in the detection and elimination of leukaemic cells. Some people’s immune systems are better at this than others’. 

The four project teams are using the latest immunotherapy techniques to reprogramme the immune system, helping it to recognise and destroy tumour cells effectively.

Project 1: Dr Persis Amrolia and Dr Nick Goulden
Immunotherapy after stem cell transplant in children with high-risk acute lymphoblastic leukaemia
Amount of grant    £348,658.

Project 2: Dr Persis Amrolia
Selective depletion of alloreactive donor T-cells to improve immune reconstitution and anti-leukaemic responses after haemopoietic stem cell transplant for acute myeloid leukaemia.
Amount of grant     £348,791.

Project 3: Dr Waseem Qasim
T cell receptor therapy against leukaemia.
Amount of grant     £210,301.

Project 4: Dr John Anderson and Dr Martin Pule
Assessment of anti-PAX5 immunotherapy for paediatric haematological and solid cancers in transgenic humanised murine model.
Amount of grant     £200,289.

Project 1: Dr Persis Amrolia and Dr Nick Goulden

Immunotherapy after stem cell transplant in children with high-risk acute lymphoblastic leukaemia.

Amount of grant    £348,658.

This project is setting out to help patients who have undergone bone marrow transplant but who are at risk of relapse.

Whilst doctors can reliably identify patients at highest risk of relapse after transplant by assessing minimal residual disease (MRD), there is currently no treatment to prevent relapse in these patients.

Patients who relapse after transplant are currently incurable and will die.

The team is using immune cells taken from the bone marrow donor and ‘reprogramming’ them to recognise a molecule called CD19 which is found on leukaemic cells.

The reprogrammed cells are infused into the child where they find the leukaemic cells, latch on to them and destroy them.

Our funding is helping them take this technique from the laboratory bench to clinical trial on the hospital wards as part of a Europe-wide initiative.

The technique will be used to treat children who develop evidence of MRD after transplant or who relapse after transplant and require a second transplant procedure.

This will be the first time that this type of gene therapy has been used in the treatment of childhood leukaemia.

Project 2: Dr Persis Amrolia

Selective depletion of alloreactive donor T-cells to improve immune reconstitution and anti-leukaemic responses after haemopoietic stem cell transplant for acute myeloid leukaemia.

Amount of grant     £348,791.

This project also focuses on patients undergoing bone marrow transplantation (BMT).

Many patients with high-risk and relapsed leukaemia are curable by BMT but do not have a matched sibling donor and are therefore transplanted from either a matched unrelated donor or a half matched donor (usually a parent).

When such transplants are done, the majority of donor immune cells must be removed from the graft to prevent a complication called graft versus host disease (GVHD) which occurs when donor immune cells attack the patient.

However, because the patients own immune cells have already been destroyed, to prevent them from rejecting the transplant, this leaves them with very little immunity for many months after the transplant. This results in a high rate of potentially life-threatening infections as well as a high risk of leukaemic relapse.

Dr Amrolia and others have investigated an approach to improving post-transplant immunity by giving back donor immune cells, having specifically removed the ‘alloreactive’ cells that cause GVHD, whilst leaving the ones that fight viruses and leukaemia.

They have already performed a clinical study in 16 children which showed that giving such “allodepleted” T-cells does improve immunity after transplants from half-matched parents.

Following this study, they have further refined their approach and designed better ways of removing the alloreactive cells so that they can give back more T cells to prevent infections and relapse without causing GVHD.

They now need to demonstrate that this approach works as effectively in the unrelated donor setting and to optimise their methods for the production of the allodepleted T-cells.

This will lay the necessary groundwork for them to proceed to a further clinical study to determine whether transferring allodepleted T-cells can safely improve anti-viral and anti-leukaemic responses in children undergoing matched unrelated or half matched donor BMT for acute myeloid leukaemia (AML).

If successful, this work should be improve the survival for children with AML by reducing viral infections and potentially also relapse post-transplant. 

Project 3: Dr Waseem Qasim

T cell receptor therapy against leukaemia.

Amount of grant     £210,301.

Immune cells (T cells) use special, customised receptors to recognise molecules on the surface of leukaemic cells which flag them as being abnormal cells. These molecules are called ‘tumour antigens’.

A tumour antigen called WT1 is expressed in a broad range of childhood leukaemias and T cell receptors which bind strongly to WT1 have been previously identified. The genetic make up of these receptors has been defined.

It is possible to transfer the genes which encode for the T cell receptors which bind most strongly to WT1 to T cells from patients lacking strong anti-leukaemia responses. This is done using disabled (harmless) viruses called ‘retroviral vectors’. The genetically modified T cells will recognise and bind to WT1, killing the leukaemic cells on which the molecules are present.

This work has got to the stage where it is about to be tested in a clinical trial in adult patients. With our funding, Dr Qasim and colleagues can now focus the approach on children and extend the technique to fight the childhood leukaemias which express high levels of WT1. 

They will incorporate recent improvements in gene transfer technologies to engineer T cells to express the best receptors against WT1.

If laboratory studies on cells collected from leukaemic children are successful, the strategy will be scaled-up for clinical testing.

Project 4: Dr John Anderson and Dr Martin Pule

Assessment of anti-PAX5 immunotherapy for paediatric haematological and solid cancers in transgenic humanised murine model

Amount of grant     £200,289.

Anderson and Pule are trying to do the same thing as Qasim but using a different molecule – PAX5. Their work is at a much earlier stage - they are trying to provide proof of concept.

PAX5 is highly expressed on B-ALL cells but, importantly, is not present on other cells, making it a good target on which to focus the immune system.

In its natural state, the immune system is not good at recognising PAX5 and so the team is aiming to reprogramme patients’ immune cells to seek out PAX5.

The team has successfully modified human T-cells to recognise cells expressing PAX5 and kill them under laboratory conditions (i.e. in a test tube).

The next step is to test it in a mouse model. That is, they will develop methods to transfer the genetic material from the modified T-cells into T-cells taken from leukaemic mice. These cells will then be transplanted back into the mice. The prediction is that cells expressing the PAX5 gene will be destroyed and the leukaemia consequently eliminated.

This work is an essential step in the design of human clinical trials. It will provide essential data on the effectiveness of the treatment and its potential toxicity before the treatment can be tried in humans. 

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