High Points and Hurdles: Immunotherapy Moves Forward

Anita T. Shaffer
Published Online: Wednesday, June 27, 2012
T lymphocytes attacking a migrating cancer cell

Illustration depicts T lymphocytes attacking a migrating cancer cell. Novel ways to improve the ability of T lymphocytes to enhance immune response are under study.

At this time last year, immunotherapy was in the limelight. Within a span of less than 12 months, the FDA had approved the first anticancer therapeutic vaccine and an antibody with a unique mechanism of action. Advocates of cancer-fighting immune strategies felt vindicated after facing skepticism and disappointment.
Today, immunotherapy is maintaining its momentum in clinical development programs, with explorations under way in many tumor types, including breast and lung cancers previously considered poor candidates for such modalities.

More than a dozen active immunotherapies are in late-stage development (Table 1 Below). And, an early-phase study into an immunotherapy agent targeting the programmed death-1 (PD-1) pathway in three different tumor types emerged as one of the most noteworthy abstracts at the American Society of Clinical Oncology (ASCO) annual meeting in June.1

At the same time, significant challenges remain in translating research discoveries into clinical use and in the marketplace, where immunotherapy has sometimes struggled to establish solid financial footing.

OncologyLive interviewed several experts on the front lines of the immunotherapy field. Here are their thoughts:

Dr. Mary L. Disis

Mary L. (Nora) Disis, MD

Professor, Medicine and Oncology, University of Washington School of Medicine, Fred Hutchinson Cancer Research Center, Seattle, WA

Mary L. Disis, MD, is a chief co-investigator of the Cancer Immunotherapy Trials Network (CITN), which links researchers at 27 institutions with the intention of creating a pipeline of agents that can move into advanced trials. The National Cancer Institute launched the network in April 2011, designating the Fred Hutchinson Cancer Research Center as its headquarters.

Disis said the rationale for establishing the CITN was “the explosion of new agents that are being developed for the immune system,” particularly after the FDA approved sipuleucel-T (Provenge) for the treatment of asymptomatic or minimally symptomatic metastatic castrate-resistant prostate cancer in April 2010 and ipilimumab (Yervoy) for unresectable and metastatic melanoma in March 2011.

“Seeing the approval of immune therapy treatments really working in patients with very advanced-stage disease, where you would expect the immune system wouldn’t be so effective, has spurred a desire to rapidly test and bring forward novel reagents across different tumors, not just melanoma or prostate cancer, that will really make a difference in the lives of patients with both advanced-stage disease and earlier-stage disease,” said Disis.

The CITN members plan to work as a unit to design trials and investigate biomarkers.

Table 1. Novel Active Immunotherapies in Late-Stage Development

Agent Tumor Type Description Sponsors/Partners Status
AGS-003
(Arcelis)
Newly diagnosed, metastatic renal cell carcinoma Autologous dendritic cells loaded with patient's messenger RNA Argos Therapeutics Phase III ADAPT trial to start mid-2012; FDA Fast Track designation
Algenpantucel-T
(HyperAcute)
Stage I/II pancreatic adenocarcinoma after surgical resection 2 separate allogenic pancreatic cancer cell lines engineered to express a-Ga NewLink Genetics Corporation Phase III under way; FDA Fast Track designation
Allovectin-7 First-line treatment for stage III/IV melanoma Plasmid/lipid-based, encoding DNA sequences for HLA-B7 and β2 microglobulin to form an MHC class I complex Vical/AnGes MC Phase III trial in final stages of patient follow-up; FDA Fast Track designation
BiovaxID Indolent follicular non-Hodgkin lymphoma Hybridoma-derived idiotype vaccine made from patient's tumor cells Biovest International/ National Cancer Institute Phase III trial completed; FDA filing planned
IMA901 Advanced/metastatic renal cell carcinoma Combination of multiple tumor-associated peptides immatics biotechnologies GmbH Phase III trial under way
Lucanix Stage IIIB/IV NSCLC after 0-5 prior chemotherapy treatments Four NSCLC cell lines gene-modified to block the secretion of TGF-β NovaRx Corporation Phase III trial under way; FDA Fast Track designation
MAGE-A3 Melanoma, NSCLC Recombinant antigen-specific cancer immunotherapeutic GlaxoSmithKline Phase III trials under way
Multikine Advanced primary squamous cell carcinoma of the oral cavity/soft palate Mixture of cytokines, including interleukins, interferons, chemokines, and colony-stimulating factors CEL-SCI Corporation/Teva Pharmaceuticals Industries/ Orient Europharma Phase III trial under way
NeuVax Early-stage, node-positive breast cancer with low-to-intermediate HER2 expression Peptide derived from HER2 combined with GM-CSF Galena Biopharma Phase III PRESENT trial under way
PROSTVAC Asymptomatic or minimally symptomatic castration-resistant prostate cancer Sequentially dosed combination of Vaccinia and Fowlpox poxviruses that encode prostate-specific antigen plus three immune-enhancing costimulatory molecules Bavarian Nordic A/S Phase III PROSPECT trial under way
Rindopepimut
(CDX-110)
Surgically resected, EGFRvIII-positive glioblastoma Consists of EGFRvIII antigen chemically conjugated to the protein keyhole limpet hemocyanin Celldex Therapeutics Phase III ACT IV Study under way
Stimuvax Unresectable stage III NSCLC in patients with response or stable disease after ≥2 cycles of chemo-radiotherapy 25-amino acid sequence of the cancer-associated marker MUC-1 in a liposomal formulation Oncothyreon/Merck KGaA Phase III START trial under way
Talimogene laherparepvec
(formerly OncoVexGM-CSF)
Unresectable stage IIIB/IIIC/IV melanoma Herpes simplex virus type 1 engineered to express GM-CSF Amgen Phase III study under way
TG4010
(MVA-MUC-IL2)
Stage IV NSCLC Modified Vaccinia virus vector expressing the MUC1 antigen and interleukin-2 Transgene/Novartis Phase IIB/III trial under way

EGFRvIII indicates epidermal growth factor receptor variant III; GM-CSF, granulocyte macrophage colony-stimulating factor; NSCLC, non-small cell lung cancer.
Sources
Cancer Research Institute and MD Becker Partners. Cancer immunotherapy: a roundtable discussion. MD Becker website. http://mdbpartners.com/?s=roundtable. Published June 30, 2011. Accessed June 6, 2012. Securities and Exchange Commission filings, annual reports, press releases for individual companies.
ClinicalTrials.gov website.

In her own work, Disis has been investigating potential immunotherapies in breast cancer for 20 years. In the past, breast tumors typically were not considered immunogenic, but research advances indicate the opposite. She believes that the immune system can be stimulated not only to treat breast cancer but also to prevent relapse.

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