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Level 1: 1 x 104 cells/kg of recipient, Level 2: 5 x 104 cells/kg, Level 3: 25 x 104 cells/kg, Level 4: 50 x 104 cells/kg, Level 5: 100 x 104 cells/kg.

Patients candidate for allogeneic transplantation who are both HLA-DPB1\*04:01 and with a HLA-DPB1\*04:01-expressing hematological malignancy (almost 100% of cases) with a donor HLA-DPB1\*04:01 negative, will be proposed to receive one single infusion of the T cell clone at 4-5 months post-transplantation, once the immunosuppression by cyclosporine and/or mycophenolate mofetil has been discontinued.

CTL 19

thierry GUILLAUME, MD

Beatrice CLEMENCEAU, PhD

Thierry GUILLAUME, MD

For several decades, allogeneic hematopoietic stem cell trans-plantation (allo-HSCT) has remained an important strategy in the management of patients with high-risk hematological malignancies. The acceptance of umbilical cord blood (UCBT) and haploidentical grafts (Haplo) as viable alternative donors for allo-HSCT has increased the options for patients with no matched donors and now ensures that a donor can be identified for virtually all patients. Relapsed disease is a principal threat to these patients and affects 30-50% of them. The therapeutic options for these relapsing patients are diverse but remain largely ineffective in altering their long-term outcomes. Therefore, pre-emptive treatment post allo-HSCT is considered.

MHC (major histocompatibility complex) class II molecules are a family of molecules normally found only on hematopoietic cells. cell-surface proteins are responsible for the regulation of the immune system in humans and are important in disease defense.

They are the major cause of organ transplant rejections. Different HLA-DPB1 alleles exist in the general population. HLA-DPB1\*04:01 is the most frequent (70.5%) while HLA-DPB1\*02:01 represents 32% and HLA-DPB1\*03:01 20%. In allo-HSCT, the donor and the recipient may express different HLA-DPB1 molecules. HLA-DPB1 matching status has an impact on GVL (graft versus leukemia) and GVHD. In recipients of HSCT, a match for DPB1 is associated with a significantly increased risk of disease relapse, irrespective of the matching status of other HLA molecules.. Therefore, one could anticipate that a mismatched of HLA class II could induce a selective GVL reactivity without GVHD.

HLA-DP-expressing B cell and myeloid malignancies can be recognized and lysed by HLA-DP-specific T cells. The majority of leukemic cells (Acute Myeloid Leukemia, Acute Lymphoid Leukemia, Chronic Lymphoid Leukemia) express HLA-DP. A T cell clone recognizing specifically HLA-DPB1\*0401 has been developed as a permanent cell line This clone has been demonstrated to be able to kill HLA-DPB1\*0401 positive leukemic cells. In addition, this clone harbors a special suicide gene allowing the destruction of the clone in presence of a specific anti-viral drug named ganciclovir.

We hypothesize that infusion of a third party suicide gene-transduced T cell clone directed against HLA-DPB1\*401 might protect against possible relapse of hematological malignancies.

We propose to inject iv escalating dose of a third party clone recognizing HLA-DPB1\*04:01, 4 to 5 months following transplantation (when immunosuppressive drugs have been discontinued) in patients HLA-DPB1\*04:01 positive with a donor HLA-DPB1\*04:01 negative to evaluate the feasibility, toxicity, benefits of this immune intervention.

Rationale Despite graft-versus-tumor effect, relapse remains one of the main causes of morbidity and mortality in allo-HSCT recipients. Forty to 50% of deaths following allo-HSCT are due to disease relapse. In case of relapse, the prognosis is very poor and disease burden remains a challenge for the use of adoptive cellular therapy alone. The 3 year overall survival (OS) in case of post-transplant relapse is dismal. The post-transplant period is characterized by a prolonged phase of immunodeficiency leading to increased vulnerability to infections and risk of relapse. For this reason, maintenance or pre-emptive therapies for patients in CR (complete remission) are now considered to prevent future relapse. Following allo-HSCT, the recognition by donor T lymphocytes of recipient HLA antigens may result in different consequences. On one side, T cells may recognize antigens present on malignant cells and eradicate residual disease or prevent tumor relapse. On the other side, injection of unselected T cells may induce a graft-versus-host-disease (GVHD).

HLA-DPB1 is one of MHC class II molecule lying centromeric to other class II loci on chromosome 6p21.3. Increase recombination events are found in the region between the HLA-DP loci and other class II loci, explaining the relative lack of linkage disequilibrium (LD) between HLA-DP (\* HLA- DP: Human Leucocytes Antigen (DP allele))and the rest of MHC haplotype. For this reason, it is difficult to find a donor matched for DPB1 in addition to other classic HLA molecules. In sibling donors, the rate of incompatibility has been estimated to be as high as 10.9% and in unrelated donors a mismatch rate can be up to 89%. HLA-DPB1 is often not taken into consideration in donor selection. However HLA-DPB1 matching status has an impact on GVL and GVHD. In recipients of HSCT, a match for DPB1 is associated with a significantly increased risk of disease relapse, irrespective of the matching status of other HLA molecules. HLA class II molecules expression is mainly restricted to hematopoietic cells. Therefore, one could anticipate that a mismatched of HLA class II could induce a selective GVL reactivity without GVHD. However, HLA class II expression can be upregulated on various tissues following exposure to pro-inflammatory cytokines with a risk of GVHD as it is the case following some conditioning regimens or infections.

The frequency of the different HLA-DPB1 alleles in the general population is well known: HLA-DPB1\*04:01 is the most frequent (70.5%) HLA-DPB1\*02:01 and and HLA-DPB1\*03:01 represent 32% and 20% respectively. 96% of leukemic cells could potentially be targeted with only three CTL clones directed against HLA-DPB1\*04:01, 03:01 and 02:01.

HLA-DP-expressing B cell and myeloid malignancies can be recognized and lysed by HLA-DP-specific CD4+ cells ( CD4+ : cluster of differentiation 4+). The majority of leukemic cells (AML, ALL, CLL) express HLA-DP. CD4+ cytotoxic T cell (CTL) clones recognizing specifically HLA-DPB1\*04:01 can be identified and have been demonstrated to be able to kill HLA-DPB1\*04:01 positive leukemic cells.

In addition, it has already been shown that HLA-DP-specific CD4+ T cells can induce graft-versus-leukemia reactivity in the presence or absence of graft-versus-host disease. In this study the presence of HLA-DP-specific CD4+ T cells correlated with the clinical response to DLI.

The team of the Inserm unit 1232 (H. Vié, B. Clemenceau, both co-investigators of this project) has developed a suicide gene-transduced CD4+ T cell clone that recognizes the HLA-DPB1\*401, which is the most frequent HLA-DPB1 allele expressed by leukemic blasts (70%). This clone has been described in detailed in :"The doubling potential of T lymphocytes allows clinical-grade production of a bank of genetically modified monoclonal T-cell populations" by Vivien R et al. Cytotherapy. 2018 Mar;20(3):436-452.

Several clinical trials have evaluated the possibility to inject, following allo-HSCT, donor lymphocytes transduced with a suicide gene either to treat tumor relapse or to accelerate the immune reconstitution. No acute infusion-related toxicity has been reported. Ganciclovir was used in some patients to control GVHD, leading to a rapid elimination of TK+ cells (tyrosine kinase +).

The clone was obtained by performing a mixed lymphocytes culture (MLR) between two populations differing only by HLA-DP, and subsequently by transducing reactive T cells with high efficiency, and finally cloning them directly, before selecting each clone for the desired characteristics. Thanks to a clinical grade Herpes-simplex-virus-TK vector, the clone harbors a suicide gene and can be killed in presence of ganciclovir (GCV).

This clone presents several important characteristics in terms of efficiency and safety. The clone is stable following thawing. It can be grown and amplified in vitro following thawing (at least more than one million times), while maintaining its cytotoxic capacity. It produces TH1-type cytokines in large amounts.

Regarding the safety of the CTL antiDP under study, we emphasized on two major points: Specificity and sensitivity to ganciclovir:

Specificity. The clone is specific for HLA-DPB1\*04:01. The clone was selected against a donor homozygous for HLA-DPB1\*04:01 (and identical for HLA-A, B, C, DQ, DR). Specificity testing confirmed the recognition of HLA-DPB1\*:04:01. Yet, HLA-DPB1 alleles described are numerous (447 proteins to date IMGT (ImMunoGeneTics database)/HLA release, www.ebi.ac.uk/ipd/index.html), and it is just impossible to anticipate the cross reactions exhaustively (beyond some against HLA-DPB1\*04:02 and HLA-DPB1\*05:01 that have been observed against particular cell lines). The risk, since we are in a context of allo-HSCT, would be the recognition of donor cells and thus a possibility of graft rejection. For this reason, we will perform a pre-inclusion testing where donor cells will be used as targets for the clone.

Sensitivity to ganciclovir (GCV) : The proliferation tests in the presence of GCV confirms the efficacy of GCV with sufficient margin according to GCV blood levels reached during a conventional treatment.

Data from our colleagues show a low number of T cells detectable during the first months post-transplant, with a relative increased of Treg cells meaning that the clone may not be eliminated rapidly by donor T-cells.

The reasons to administer a suicide gene-transduced CD4+ T cell clone recognizing HLA-DPB1\*04:01 following allogeneic transplantation can be summarized in the following points :

1. Relapse of the hematological malignancy remains a serious concern in these types of transplantation.

3. The immune reconstitution is very delayed allowing for injection of a third party T cell clone.

4. In case of GVHD following the CTL infusion, the CTL clone can be rapidly eliminated using ganciclovir.

Hypothesis We hypothesize that the infusion of a third party suicide gene-transduced T cell clone directed against HLA-DPB1\*04:01 following allogeneic transplantation can be safe and might protect against possible relapse of hematological malignancies

Detailed description of the methodology (number of necessary subjects) Patients candidate for allogeneic transplantation who are both HLA-DPB1\*04:01 and with aHLA-DPB1\*04:01-expressing hematological malignancy (almost 100% of cases) with a donor HLA-DPB1\*04:01 negative, will be proposed to receive one single infusion of the T cell clone at 4-5 months post-transplantation, once the immunosuppression by cyclosporine and/or mycophenolate mofetil has been discontinued. The expression of HLA-DPB1\* by tumor cells will be checked by cytometry or immunohistochemistry. Any possible cross-reactivity of the clone against donor cells will also be excluded

A standard 3 + 3 phase 1 dose-escalation study will be used:

Level 1: 1 x 104 cells/kg of recipient, Level 2: 5 x 104 cells/kg, Level 3: 25 x 104 cells/kg, Level 4: 50 x 104 cells/kg, Level 5: 100 x 104 cells/kg.

Conditioning regimens : no restriction

The use of DLI in case of mixed chimerism or relapse is permitted after the clone infusion if necessary. In case of acute GVHD post CTL clone infusion, ganciclovir will be administered (at the dose of 5 mg/kg twice daily) for 14 days.

Biological, T cell clone

A standard 3 + 3 phase 1 dose-escalation study will be used:

Level 1: 1 x 104 cells/kg of recipient, Level 2: 5 x 104 cells/kg, Level 3: 25 x 104 cells/kg, Level 4: 50 x 104 cells/kg, Level 5: 100 x 104 cells/kg.

Phase I Study of CTL Anti-DP Infusion Post-hematopoietic Stem Cell Transplantation

A Phase 1 Dose-escalation Study Testing the Feasibility and the Tolerance of Infusion of a Specific Third Party Suicide Gene-transduced Anti-HLA-DPB1*0401 CD4+ T Cell Clone in HLA-DPB1*04:01 Positive Tumor Recipients Receiving an Allotransplant From a HLA-DPB1*04:01 Negative Donor.

the most likely side effects of the injection of the clone is the induction of an acute GVHD (severity measured by organ staging and overall clinical grading).

acute GVHD will be evaluated for each patient. Maximal tolerated dose is defined as : none acute GVHD for 3 patients on 3 or for at least 5 patients on 6.

A standard 3 + 3 phase 1 dose-escalation study will be used:

Level 1: 1 x 104 cells/kg of recipient, Level 2: 5 x 104 cells/kg, Level 3: 25 x 104 cells/kg, Level 4: 50 x 104 cells/kg, Level 5: 100 x 104 cells/kg.

The survival of the clone will be tracked by PCR (polymerase chain reaction) during the 60 first days post injection as well as 6 and 12 months post injection in the blood and in the marrow

T cell reconstitution will be evaluated by measuring the levels of CD4+, CD8+, Natural Killer cells

cumulative incidence of acute and chronic GVHD

for lymphoma patients in partial response before allograft

INSERM U01232 CRCINA

Nantes University Hospital

Neoplasms

Heart and Blood Diseases

Immune System Diseases

Rare Diseases

Multiple Myeloma

Neoplasms, Plasma Cell

Neoplasms by Histologic Type

Hemostatic Disorders

Blood Coagulation Disorders

Vascular Diseases

Paraproteinemias

Blood Protein Disorders

Hemorrhagic Disorders

Lymphoproliferative Disorders

Immunoproliferative Disorders

Molgramostim

Sargramostim

Vaccines

Immunologic Factors

After DLI on same day, patients receive vaccine according to donor randomization (the same type of vaccine that their donors received).

Donor Group 1: (non-specific vaccination) vaccinated with KLH only vaccine 0.5 cc subcutaneously, 3 times on weeks -8, -6 and -2 prior to donor lymphocyte collection.

Donor Group 2: (myeloma specific vaccination) vaccinated with KLH-id vaccine 0.5 cc subcutaneously, 3 times on weeks -8, -6 and -2 prior to donor lymphocyte collections.

Donor: 0.5 cc subcutaneously, 3 times on weeks -8, -6 and -2 prior to lymphocyte collection.

Patient: 0.5 cc subcutaneously, 3 times immediately after infusion of donor cells (DLI), and again 4 and 8 weeks post DLI.

KLH Vaccine

Donor: 0.5 cc subcutaneously, 3 times on weeks -8, -6 and -2 prior to donor lymphocyte collection.

Patient: 0.5 cc subcutaneously, 3 times immediately after infusion of donor cells (DLI), and again 4 and 8 weeks post DLI.

KLH-id Vaccine

250 mcg/m2 subcutaneously daily for 4 days after each vaccine

GM-CSF

Day 0 (day of lymphocyte collection) donors undergo a steady state pheresis to obtain lymphocytes.

Apheresis

Day 0, infusion to patient of collected donor cells.

Donor Lymphocyte Infusion (DLI)

Muzaffar H. Qazilbash, MD

The goal of this clinical research study is to learn if vaccinating a donor with your purified myeloma protein and then injecting it back into you will help your immune system control the multiple myeloma.

A vaccine will be made of tumor protein taken from your plasma (liquid part of the blood) and KLH (a protein designed to increase the immune response of the vaccine). By vaccinating your brother or sister with protein made from the tumor, researchers hope to increase the antitumor effect of the stem cells. KLH is used to help the immune response.

Study Treatment Schedule:

If you are found to be eligible to take part in this study, you and your brother or sister will receive a vaccine with KLH. This research involves various steps. In Step 1, a large sample of your plasma will be collected through a vein using a blood separator device. This plasma will be sent to the MD Anderson GMP lab to prepare the vaccine. It takes about 3 months to create your myeloma-specific vaccine. It takes about 3 months to prepare enough vaccine for the next phases of the study.

In Step 2, your brother or sister will receive the vaccine with KLH as an injection under the skin 8 weeks, 6 weeks, and 2 weeks before collection of his/her lymphocytes (immune fighting cells). After each injection, your brother or sister will receive an injection of a medication called GM-CSF that helps the body's response to the vaccine. GM-CSF is given under the skin near the site of the vaccination every day for 4 days, starting the day of the vaccination.

In Step 3, your brother or sister will have apheresis. During apheresis, their blood is passed through a "cell separator" and the lymphocytes (immune fighting cells) are collected. A portion of these cells will be given to you on this day. You will get these cells through a vein while the remainder is stored and frozen for research and/or use later on if you fail to respond to the first infusion.

In Step 4, you will receive the vaccine with KLH. It will be given under the skin immediately after you get the infusion of donor cells, and again 4 and 8 weeks after the lymphocyte infusion. After each vaccine, you will receive an injection of a medication called sargramostim (GM-CSF) that helps the body's response to the vaccine. GM-CSF is given under the skin near the site of the vaccination every day for 4 days, starting the day of the vaccination.

If after 6 months you are not responding to the vaccine, you will be allowed to receive 3 additional vaccines, as long as you did not develop graft versus host disease or any other serious side effects to the first vaccine. The vaccines and follow-up schedule is exactly like the first.

Study Visits:

Within 10 days before you receive the infusion of your donor's cells and within 72 hours before each vaccine injection, the following tests and procedures will be performed:

* Your medical history will be recorded.
* You will have a physical exam, including measurement of your vital signs.
* You will be checked for possible reactions to your treatment, including graft-versus-host disease (GVHD). Infused donor cells may react against your body.
* You will be asked about any side effects you may have had since the first vaccine injection.
* Blood (about 6-12 teaspoons) will be drawn for routine tests and to check your kidney and liver function, as well as the status of your immune system. Part of the blood will be used to test for CMV, hepatitis B, hepatitis C, HIV, HTLV, syphilis, West Nile virus, sickle cell anemia, and Chagas disease. Part of the blood collection will also be used for a pregnancy test for females who are able to have children. To continue to receive infusions of your donor's cells, the pregnancy test must be negative.
* You will have x-rays or bone marrow aspirates and biopsies to assess the response of your disease.

These visits will require 1 day of your time.

Long-Term Follow-Up:

Once a month during Months 3, 6, 12, 18, and 24 months after your last vaccine, the following tests and procedures will be performed:

* Your medical history will be recorded.
* You will have a physical exam, including measurement of your vital signs.
* You will be checked for possible reactions to your treatment, including GVHD.
* Blood (about 6-12 teaspoons) will be drawn to check your kidney and liver, function as well as the status of your immune system. Part of the blood collection will also be used for a pregnancy test for females who are able to have children. To continue to receive infusions of your donor's cells, the pregnancy test must be negative.
* You will have a bone marrow biopsy and aspiration. It may be repeated more often, if your doctor thinks it is needed.

If you are not able to return to MD Anderson, your study doctor may agree to allow you to have these tests and procedures at your local doctor's office. Your local doctor will need to send the results to research staff at MD Anderson.

Once a year, starting 2 years after you receive the last infusion of your donor's cells, you will be contacted by phone to check on your health status.

Length of Study Participation:

You will be considered off study after 5 years. You will be taken off study at any time if lymphocytes cannot be collected, not enough lymphocytes can be collected, your doctor thinks it is needed, the recipient is not able to receive the vaccine, the study doctor thinks it is in your best interest, you need a treatment that is not allowed while on this study, you are unable to keep appointments, or you have intolerable side effects.

This is an investigational study. The myeloma-specific vaccine is not FDA approved or commercially available, and it has been authorized for use in research only. Up to 10 patients will take part in this study. All will be enrolled at MD Anderson.

Trial of ID-Specific Donor Vaccinated Lymphocyte Infusion for Patients With Myeloma Relapsing or Failing to Achieve a Complete Remission After an Allogenic Transplant

Phase II Trial of ID-Specific Donor Vaccinated Lymphocyte Infusion for Patients With Myeloma Relapsing or Failing to Achieve a Complete Remission After an Allogenic Transplant

PR defined as 50% reduction disease including serum monoclonal paraprotein and CR defined as absence of original monoclonal paraprotein in serum and urine.

M.D. Anderson Cancer Center

Recipient

Donor

Total

Age, Categorical

Sex: Female, Male

Race (NIH/OMB)

United States

Region of Enrollment

Qazilbash,Muzaffar,M.D. / Stem Cell Transplantation

The donor participant was to supply the cell product to manufacturer the vaccine. The donor has no disease and therefore cannot be analyzed for a response.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Phase I Study of CTL Anti-DP Infusion Post-hematopoietic Stem Cell Transplantation	NCT04180059	Haematologic Di...	CTL 19	18 Years - 75 Years	Nantes University Hospital
Trial of ID-Specific Donor Vaccinated Lymphocyte Infusion for Patients With Myeloma Relapsing or Failing to Achieve a Complete Remission After an Allogenic Transplant	NCT01174082	Myeloma	KLH Vaccine KLH-id Vaccine GM-CSF Apheresis Donor Lymphocyt...	18 Years - 70 Years	M.D. Anderson Cancer Center

Spots Global Cancer Trial Database for lymphocyte infusion