A vaccine that delivers an antigen to dendritic cells, in turn activating killer T cells that can target specific cancers, is the subject of two ongoing clinical trials. The vaccine, LV305, is a lentiviral gene vector that specifically binds to dendritic cells in a patient’s body via surface receptor CD209 (also called DC-SIGN) and introduces the full length of the NY-ESO-1 antigen into these cells. The dendritic cells then present the antigen to CD8-positive T lymphocytes via the major histocompatibility (MHC) class I molecules on the cell surface. The activated CD8+ cells can then recognize and attack cancer cells that express NYESO-1.
A target for immunotherapy
The cancer/testis antigen NY-ESO-1 is highly expressed in spermatogonia during embryogenesis, but in adults the antigen is expressed only in testicular germ cells and in several types of cancer. The highest rates of NY-ESO-1 have been seen in certain sarcoma subtypes: 80%–100% of myxoid/round cell liposarcomas and synovial sarcomas express NY-ESO-1. The antigen is also expressed in about 40% of melanomas and up to 20% of breast, ovarian, and non–small cell lung cancers.
NY-ESO-1 is considered a good target for immunotherapy because NYESO-1–expressing cancer cells—but not healthy germ cells—express MHC restriction elements that are recognized by cytotoxic T lymphocytes. “If you have a T cell response against NY-ESO-1, there should be no negative immunological effects in the body except against the tumor,” said Neeta Somaiah, M.D., an assistant professor in the Department of Sarcoma Medical Oncology at The University of Texas MD Anderson Cancer Center. LV305 is one of several new treatments aimed at inducing such a response.
Dr. Somaiah said that LV305 compares favorably with other technologies that target NY-ESO-1–positive tumors. One such technology is adoptive T cell therapy, in which T cells that have been genetically modified to recognize a specific peptide of NY-ESO-1 are infused into the patient. Although the adoptive T cell therapy has shown promising results, it is human leukocyte antigen (HLA)–specific. Most adoptive T cell therapy approaches target the NY-ESO-1 peptide presented by HLAA* 02:01 and therefore are limited to patients with that specific HLA type. The technique also requires specialized centers for the expansion and administration of T cells. In contrast, the LV305 vaccine could be administered at any center and, since the vaccine induces in T cells the expression of full-length NY-ESO-1, is not restricted by HLA type.
Last year, an ongoing multi-institutional, first-in-human trial of LV305 began enrolling patients with locally advanced or metastatic sarcoma, melanoma, ovarian cancer, non–small cell lung cancer, or breast cancer whose biopsy specimens show NY-ESO-1 expression in at least 5% of the tumor cells. Another eligibility requirement is low tumor burden. “Patients with bulky or rapidly progressing disease might be immunosuppressed and might not be able to generate an immune response fast enough to see a benefit from LV305 as a single agent,” said Dr. Somaiah, MD Anderson’s principal investigator for the trial.
Patients in the open-label study receive 3 or 4 intradermal injections of LV305 given at 3-week intervals. In the trial’s dose escalation arm, which has completed enrollment, patients received doses of 1 x 108, 1 x 109, or 1 x 1010 vector genomes per injection.
All 12 patients in the dose escalation arm had sarcoma with NY-ESO-1 expression levels ranging from 6% to 100%. Eleven of these patients completed the full course of LV305 treatment. One patient had progressive disease after his second LV305 injection and discontinued the trial to begin a different therapy.
Dr. Somaiah, who presented the trial’s preliminary results at the 2015 American Society of Clinical Oncology Annual Meeting, said that eight of the 11 patients for whom immunological data were available had a doubling in the number of CD4+ cells and/or CD8+ cells against NY-ESO-1 (five had a CD4+ cell response and six had a CD8+ cell response). Four of the six patients with a CD8+ cell response received the middle or high dose of LV305, indicating a possible dose-response relationship similar to that seen in preclinical models. Additional immunological studies in one patient revealed an increase not only in the number of NY-ESO-1–specific CD8+ cells but also in their binding affinity for NY-ESO-1 and their ability to recognize multiple NY-ESO-1 epitopes.
Eight of the 12 patients had stable disease at last follow-up, and one patient had tumor regression of around 14%. “The clinical and immunological response data are encouraging and warrant further study,” Dr. Somaiah said.
As expected, side effects were minimal and included mild discomfort at the injection site and fatigue. No dose-limiting toxic effects were observed, so the highest dose of LV305, 1 x 1010 vector genomes, will be used for the ongoing expansion arm of the trial.
The expansion arm of the first-in-human trial will include six patients each with sarcoma, melanoma, non–small cell lung cancer, and ovarian cancer. The sarcoma cohort is full; however, Dr. Somaiah said, sarcoma patients whose tumors express NYESO-1 may be eligible for a new combination therapy trial that recently began enrollment at MD Anderson and other institutions.
In the new trial, LV305 is given sequentially with G305, a full-length NY-ESO-1 protein mixed with a synthetic TLR4 agonist, glucopyranosyl lipid A. In an early trial, G305 demonstrated NY-ESO-1–specific CD4+ cell and antibody responses in patients with NY-ESO-1–positive tumors.
The sequential use of LV305 and G305 (called CMB305) is designed to produce NY-ESO-1–specific CD8+ cell, CD4+ cell, and antibody responses. The eligibility requirements of the CMB305 trial are similar to those of the LV305 monotherapy trial.
Future studies may combine CMB305 with a programmed cell death 1 (PD-1) inhibitor in patients with NY-ESO-1–positive tumors.“
Our early results show that LV305 is safe and generates an immune response,” Dr. Somaiah said. “Future studies will determine the best combination and sequence of agents to generate an effective and durable immune response with a robust antitumor effect.”
For more information, contact Dr. Neeta Somaiah at 713-792-3626.
OncoLog, September 2015, Volume 60, Issue 8