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WT1 Heteroclitic Epitope Immunization Following ASCT in Patients with High-Risk Multiple Myeloma
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Dr. Guenther Koehne discusses WT1 Heteroclitic Epitope Immunization Following ASCT in Patients with High-Risk Multiple Myeloma at ASCO 2017. For the ability to view on your mobile phone please visit us at MinuteCE.com.

This transcript is software driven, please understand there may be errors.  Should any inaccuracies or omissions be found, please notify transcripts@MedEdOTG.com for correction.

Hello my name is Guenther Koehne. I'm an attending Physician of the Bone Marrow Transplantation Service at Memorial Sloan Kettering Cancer Center. Today I'm going to introduce you to some new results that we developed in the past, by utilizing a new vaccine and the administration, following an autologous transplantation for multiple myeloma.

The Wilms’ tumor 1 or WT1 protein is a zinc finger transcription factor that has been implicated in cell proliferation, differentiation, apoptosis and organ development. Initially it was described as a tumor suppressor gene but later identified as a true oncogene. My own group has previously demonstrated the over expression of WT1 in multiple myeloma cells and the formation of a WT1 peptide fragment complex on the engagement interface surface between malignant plasma cells and T cells in multiple myeloma patients.

We also previously described development of WT1 specific T cell responses in myeloma patients, following donor lymphocyte infusions, after an allogeneic T cell, previous stem cell transplantation which was associated with a graft-versus-myeloma effect.

Now we tested a new vaccine called Galinpepimut-S or GPS which is a first in class WH1 heteroclitic peptide mixture of two native and two synthetic WT1 peptide sequences. The synthetic heteroclitic peptides which bear point mutations were created to simulate both classes of differentiation of CD4 and CD8 T cell responses as shown in Figure 1.

In Table 1 we show the summary of four peptides that are part of the vaccine. We can see that in, for example, the first vaccine, the Y or the RMF peptide has been modified through the Y amino acid which is the heteroclitic nature of this peptide, which also has been mutated in the last of these four peptides. All the peptides are given as, together with montonites subcutaneously, after priming the site with GMCSF.

In Figure 1, you see the principle of the heteroclitic technology, where the heteroclitic peptide contained within the vaccine is modified to induce a stronger binding to the HLA groove of the dendritic cells or antigen presenting cells and thus inducing or initiating a stronger T cell response. This stronger T cell response, then leads to recognition of the non-mutated peptide on the plasma cell.

The principle of the clinical trial is shown in Figure 2, where we are administering the standard of care of induction chemotherapy, followed by autologous stem cell transplantation and then initiate within 22 days of the autologous transplant, the administration of the GPS vaccine, which is given initially every two weeks times six doses. And then, the patient had the choice to continue with the vaccination, another six doses every four weeks apart.

The key eligibility criteria’s are shown on the poster and the only criteria shown here is the patient needed to be older than 18 years old, Karnofsky performance status of better than 50% and the rest of the criteria as per standard of care.

The clinical trial design also included that the protein expression of the WT1 peptide was needed to be assessed by immunohistochemistry. We included the WT1 specific immune responses at an end point, which were measured by intracellular interfering gamma analysis upon stimulation of peripheral blood mononuclear cells pulsed with a total pool of overlapping 15mers which are 15 amino acids long or each of the four peptides contained within the GPS vaccine.

Patient demographics and baseline characteristics are shown in Table 2. For the purpose of this presentation I'd just like to point out that all of our patients had high risk cytogenetics and thus belong into the group of high risk multiple myeloma patients.

The results are summarized in Figure 3 and Figure 4. In Figure 4 you can see that the progression free survival or the median progression free survival was 23.6 months and the overall survival not reached, this is an impressive outcome compared to historical controls. Since this was not a randomized trial, the only measurement was to compare to historical controls which in the same category of patients with similar treatments, that is induction chemotherapy or autologous transplant and maintenance treatment ranges usually at 9.6 months.

You can also see in Figure 3 that following the administration of the vaccine, the percentage of patients that achieved a complete remission increased from 31.6% following the autologous transplant to 56 and then subsequently to 53% after the administration of the vaccines.

Most importantly as shown in Figure 5 the immune responses that we obtained were very impressive. Immune responses were contained of CD4 responses as well as CD8 responses. Most importantly the immune responses that we achieved were not only targeting the heteroclitic peptide but we can certainly demonstrate that also the native peptide expressed on the myeloma cells induced a significant CD4 and CD8 response.

In patient number 19 for example, you can see that after six doses and moreover after 12 doses of the vaccine there was a steady increment of the immune responses, primarily consisting of CD8 responses as expected in this patient. And in patient number 16 we demonstrate an immune response that is primarily targeting the 122A1 peptide which is a long peptide and for this reason, as expected, we also see a dominance of the CD4 responses.

The safety of this vaccine can be summarized by no severe adverse events. The only observation that we obtained was that there was a nodule formulation or local nodularity at the site of the injection site, sometimes little redness around it which resolved within two to six weeks usually.

In summary we can demonstrate that the administration of this new WH1 heteroclitic peptide, administered in patients with multiple myeloma following autologous transplantation demonstrates encouraging median progression free survival of currently 23.6 months. As I've pointed out, historical controls such as the one in the Medical Research Council Myeloma IX study had in a similar patient population a progression free survival of 9.3%

Most importantly this immunotherapeutic is an off the shelf approach, can be easily administered at any given time to the patients. We demonstrate that a WH1 specific CD4 and CD8 response is elicited in 16 of 18 patients analyzed so far and with this we plan a larger phase 2 trial to potentially randomize maintenance treatment following autologous transplantation, lenalidomide versus lenalidomide plus the GPS vaccine as the next step.

With that I thank you for your attention and listening to my presentation, thank you.NULL