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Dr. Rapoport- Combination Immunotherapy After ASCT for Multiple Myeloma (MM) Using MAGE-A3/Poly-ICLC Immunizations Followed by Vaccine-Primed and Activated Autologous T-Cells
Aaron Rapoport, MD
University of Maryland
Baltimore, MD
Program: Oral and Poster Abstracts
Type: Oral
Session: 723. Clinical Allogeneic and Autologous Transplantation - Late Complications and Approaches to Disease Recurrence: Improving Transplant Outcomes Through Immunomodulation
Monday, December 10, 2012: 7:45 AM
C108-C109, Level 1, Building C (Georgia World Congress Center)

Aaron P. Rapoport, MD1, Nicole A. Aqui, MD2*, Edward A. Stadtmauer, MD3, Ashraf Z. Badros, MD4, Dan T. Vogl, MD, MSCE5, YinYan Xu2*, Brendan M Weiss, MD3, Ling Cai, PhD6*, Hong-Bin Fang, PhD7*, Elizabeth Veloso, RN, JD8*, Zhaohui Zheng, MA2*, Saul Yanovich, MD9, Gorgun Akpek, MD, MHS1*, Sunita Philip10*, Kathleen Ruehle, RN9*, Kelly-Marie Betts, MS1*, Anne Chew, PhD11*, Holly McConville, RN, BSN3*, Sandra Westphal1*, Scott Strome12*, Andres Salazar, MD13*, Bruce L. Levine, PhD2* and Carl H. June, MD3

1Greenebaum Cancer Center, University of Maryland, Baltimore, MD
2Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA
3Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA
4Department of Medicine, University of Maryland Greenebaum Cancer Center, Baltimore, MD
5Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
6Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD
7Epidemiology and Public Health, Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD
8University of Pennsylvania, Philadelphia, PA
9University of Maryland, Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD
10University of Maryland , Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD
11Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA
12Otolaryngology, University of Maryland, Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD
13Oncovir, Washington,DC, DC

Background: Autologous stem cell transplantation (ASCT) for MM leads to complete responses in ~20-40% of patients but rare cures. Patients with rapid recovery of T cells post ASCT may have improved outcomes suggesting possible immune mediated tumor control.  We have shown that adoptive T-cell transfers after ASCT for MM using vaccine-primed and ex-vivo costimulated autologous T-cells in combination with pre- and post-transplant immunizations using a tumor antigen vaccine (+ GM-CSF and montanide) led to vaccine-directed T-cell responses in about 1/3 of patients and enhanced recovery of polyclonal T and B cell counts and function.  We hypothesized that addition of Poly-ICLC (Hiltonol®) – a TLR-3 agonistic vaccine adjuvant could increase tumor antigen vaccine responses through better priming and boosting. 

Methods: We report interim results of a Phase II clinical trial (NCT01245673) evaluating safety and activity of autologous T cells primed in-vivo with a MAGE-A3 multipeptide vaccine (Orphan Drug Designation: GL-0817) mixed with GM-CSF and Poly-ICLC (Hiltonol®) +/- montanide. Inclusion criteria included measurable disease or high-risk cytogenetics. MAGE-A3 is expressed in ~50% MM cases and more frequently in relapsed/extramedullary/proliferative disease. The MAGE-A3 vaccine has 2 HLA-A2-restricted class I peptides and 1 promiscuous class II peptide linked to an HIV-1-TAT membrane translocation sequence (Trojan peptide) to enhance peptide presentation. Vaccine-primed T cells were collected by leukapheresis, costimulated and expanded ex-vivo using anti-CD3/anti-CD28 mAb conjugated beads. T-cells were infused at day +2 after ASCT followed by booster immunizations at days 14, 42, 90, 120 and 150 post-transplant.  Lenalidomide maintenance was started at day +100.  Patients were evaluated for MM responses in accordance with IMWG criteria at days 60, 100, 180 post-transplant and Q3 months thereafter.  T-cell and B-cell responses to the vaccine were evaluated by IFN-g or IL-2 cytokine production (all patients), dextramer binding to CD8 cells (HLA-A2 positive patients) and ELISA antibody assays at days 14, 60, 100 and 180 post-transplant. 

Results: 25 patients were transplanted on study. At a median followup of 6 months (range 2-18 months), 24 patients are surviving while 1 patient relapsed at about day +60 and died.  Four additional patients have relapsed at 7,9,18 and 18 months post-transplant, yielding a 1-year Kaplan-Meier EFS of 77%.  Of the 16 patients evaluable for response at day 100, 7/16 (44%) had CR/nCR using the study enrollment (post-induction) myeloma markers as a baseline while at day 180, 7/13 (53%) had CR/nCR.  T-cell infusions were well-tolerated with no probable/definite grade 3 or higher toxicities.  Vaccinations were associated with > 50 mm injection site reactions (redness, induration or both) after 1 or more immunizations in the majority of patients.  Two patients developed large and prolonged inflammatory reactions which evolved into sterile abscesses.  These resolved over 2-3 months with conservative management but as a result montanide was eliminated from the vaccine formulation for patients 11-25.  Thereafter vaccine reactogenicity was decreased with no additional sterile abscesses. Of 16 patients tested for immune responses to date, 2 patients were unevaluable due to poor sample viability. Dextramer staining demonstrated MAGE-A3-specific CD8 T-cells in 4/4 (100%) of evaluable HLA-A2+ patients.  Cytokine production in response to MAGE-A3 stimulation was seen in 11/14 (79%) patients; responses usually peaked at day 100 or day 180.  Robust MAGE-A3 antibody responses were detected in 7/9 patients who received montanide in the vaccine formulation but in 0/7 patients who did not. 

Conclusions: Combination immunotherapy using a MAGE-A3 multipeptide tumor antigen vaccine plus vaccine-primed and costimulated autologous T-cells after ASCT for MM is well-tolerated and associated with encouraging early clinical responses.  The addition of Poly-ICLC (Hiltonol®) to the vaccine formulation was associated with a high frequency of post-ASCT T-cell functional responses.  The combination of Poly-ICLC +GM-CSF + Montanide led to robust injection site reactions that were occasionally severe and prolonged.  Elimination of the montanide reduced injection site reactogenicity but may also have compromised the B-cell responses to the tumor antigen vaccine. 

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