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Rising out of the ASH
February 2016
by Jeffrey Bouley  |  Email the author
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ORLANDO, Fla.—Of the many things to come out of the annual meeting of the American Society of Hematology (ASH) in Florida recently were preclinical oncology highlights from West Coast-based Immune Design for intratumoral administration related to G100 in a preclinical model of lymphoma and from East Coast-based bluebird bio for its B cell maturation antigen (BCMA) program.
 
For its part, clinical-stage immunotherapy company Immune Design announced the presentation of data on its candidate G100 that demonstrated both direct and abscopal (indirect) tumor regression, as well as tumor-specific, long-term immune protection. G100 is Immune Design’s intratumoral TLR4 agonist-based product candidate and is currently in clinical trials. The research—authored by Dr. Ronald Levy and Idit Sagiv-Barfi of Stanford University and Hailing Lu, Jessica Hewitt, Frank Hsu and Dr. Jan ter Meulen of Immune Design—investigated the therapeutic impact and immune response of intratumoral administration of G100 in a preclinical model of lymphoma.
 
Results demonstrated:
  • Tumor regression of 60 percent to 100 percent across the animal models
  • Tumor growth inhibition reported in both injected tumors as well as uninjected tumors (abscopal effects)
  • Responders remained tumor-free at least three months post-G100 treatment and were resistant to secondary challenge with the same tumor type
  • Tumor-specific, systemic CD8 T cell responses were induced and shown to mediate antitumor protection
  • Combination with immune checkpoint modulation led to enhanced tumor protection and improved survival
  • G100 had an impact on the tumor microenvironment, changing it from a non-inflammatory state (“cold” tumor microenvironment) to an inflamed state (“hot” tumor microenvironment).
“These data demonstrate the ability of G100 to alter the tumor microenvironment and generate a systemic T cell-based antitumor response that is both specific and long-lasting,” said Levy, chief of the Division of Oncology at the Stanford University School of Medicine. “G100, either alone or in combination with immune checkpoint modulators, according to this model, may hold potential as a treatment for lymphoma patients.”
 
“These findings build on the strong set of preclinical and clinical data that support the ability of Immune Design’s G100 product candidate to have an impact on the immunotherapy landscape, including in combination with other immuno-oncology approaches,” said Meulen, chief scientific officer at Immune Design. “These data provide support for our planned clinical trial in patients with follicular non-Hodgkin’s lymphoma receiving local radiation, with or without the anti-PD-1 therapy, Keytruda, pursuant to our collaboration with Merck.”
 
G100 is a product candidate generated from the company’s GLAAS discovery platform, and includes a specific formulation of glucopyranosyl lipid A (GLA), a synthetic, toll-like receptor-4 (TLR-4) agonist. G100 is part of Immune Design’s intratumoral immune activation, or “endogenous antigen” approach to treating cancer, which leverages the activation of dendritic and other immune cells in the tumor microenvironment to potentially create a robust immune response against the tumor’s preexisting diverse set of antigens. Preclinical and clinical data have demonstrated the ability of G100 to activate dendritic cells in tumors and to increase antigen-dependent systemic humoral and cellular Th1 immune responses.
 
A Phase 1 study of G100 in patients with Merkel cell carcinoma recently completed enrollment. A Phase 1 study evaluating intratumoral G100 in patients with follicular non-Hodgkin’s lymphoma is currently enrolling patients.
 
Meanwhile, bluebird bio Inc., a clinical-stage company committed to developing potentially transformative gene therapies for severe genetic diseases and T cell-based immunotherapies for cancer, announced preclinical data from its anti-BCMA oncology program at the ASH meeting.
 
“We believe the unique science and translational gene therapy platforms we have built differentiate bluebird bio in the oncology field and have the potential to yield important new therapies for patients living with cancer. Our three oncology posters at ASH this year, covering critical basic research, translational and manufacturing aspects of our T cell oncology pipeline, demonstrate the strength of our T cell immunotherapy translational science,” said Dr. Rob Ross, head of oncology at bluebird bio. “We are also excited to see the first anti-BCMA clinical data from Dr. Jim Kochenderfer of the National Cancer Institute … We believe these data provide excellent proof of concept for bb2121 and are pleased that Jim will serve as one of the principal investigators for our Phase 1 study of bb2121.”
 
In one of the three posters Ross noted, presented by Dr. Molly Perkins, bluebird bio explored the potential for culture modifications to improve the therapeutic potential of CAR T cells without adding complexity to manufacturing. The company tested this hypothesis using CAR T cells specific to B cell maturation antigen (BCMA) manufactured using standard IL-2 culture with an inhibitor of PI3K added to the media, or with IL-7 and IL-15, in place of IL-2.
 
In an in-vivo aggressive lymphoma model, mice treated with anti-BCMA CAR T cells cultured only with IL-2 experienced no effect on tumor growth and succumbed to the tumors within two weeks after treatment; anti-BCMA CAR T cells grown in IL-7 and IL-15 also did not affect tumor growth. In contrast, mice treated with anti-BCMA CAR T cells cultured with IL-2 and an inhibitor of PI3K experienced complete and long-term tumor regression.
 
In an in-vivo multiple myeloma model, mice received a single administration of anti-BCMA CAR T cells cultured under various conditions; all treatment groups demonstrated tumor regression regardless of culture conditions. In a model of tumor relapse, two weeks after tumor clearance, surviving mice were re-challenged with the same multiple myeloma tumors on the opposite flank; only animals that had been treated with anti-BCMA CAR T cells cultured with the PI3K inhibitor were able to resist subsequent tumor challenge.
 
These data suggest that inhibition of PI3K during ex-vivo expansion may generate a superior anti-BCMA CAR T cell product for clinical use; this approach could potentially apply to the manufacture of CAR T cell therapies against other oncology targets.
 
In the second poster, presented by Dr. Alena Chekmasova, bluebird bio noted it had developed a CAR-targeting BCMA (bb2121) that consists of an extracellular single chain variable fragment scFv antigen recognition domain derived from antibodies to BCMA linked to CD137 (4-1BB) co-stimulatory and CD3zeta chain signaling domains. Based on receptor density quantification, bb2121 can recognize tumor cells expressing fewer than 1,000 BCMA molecules per cell.
 
In a preclinical BCMA+ multiple myeloma xenograft model, a single intravenous administration of bb2121 anti-BCMA CAR T cells resulted in rapid and sustained elimination of the tumors with 100-percent survival, while a month-long course of anti-myeloma therapy Velcade (bortezomib) only delayed tumor growth.
 
In the third poster, presented by Graham W.J. Lilley, T cells transduced with varying amounts of virus to yield different amounts of CAR surface expression were diluted with donor-matched untransduced cells to achieve a uniform population of T cells containing 26 + 4 percent anti-BCMA CAR T cells. When exposed to tumors, these CAR T cell populations exhibited no difference in cytotoxicity against BCMA-expressing cells.
 
All T cell productions easily achieved a level of anti-BCMA CAR expression that resulted in potent anti-BCMA activity, the company reported, thus potency of the final drug product was shown to be independent of total anti-BCMA CAR expression on the cell surface.
 
These data suggest that the bluebird bio T cell manufacturing process has the potential to overcome significant challenges associated with personalized medicine by reducing the effects of variability while maintaining potency in autologous cellular drug product manufacturing.
 
Code: E021603

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