Activity In Solid Malignancies Research Articles

Abstract IA20: Updates on CAR T Cells

Abstract The emergence of immune-oncology as the first broadly successful strategy for metastatic cancer will require clinicians to integrate this new pillar of medicine with the pillars of chemotherapy, radiation, and targeted small-molecule compounds. Chimeric antigen receptor (CAR) T cells have proven that engineered immune cells can serve as a powerful new class of cancer therapeutics. Adoptive immunotherapy retargeting T cells to CD19 via a chimeric antigen receptor (CAR) is an investigational treatment capable of inducing complete tumor regression of B-cell malignancies when there is sustained survival of infused cells. Clinical experience has helped to define the major challenges that must be met to make engineered T cells a reliable, safe, and effective platform that can be deployed against a broad range of tumors. The emergence of synthetic biology approaches for cellular engineering provides the field with a broadly expanded set of tools for programming immune cells. In this presentation, I will discuss how these tools could be used to design the next generation of smart T-cell precision therapeutics. We have been exploring in preclinical models and clinical trials methods to synthetically enhance T-cell antitumor efficacy by transfer of genetically engineered T cells. Infusions of chimeric antigen receptor (CAR) T cells can result in remissions in patients with hematologic malignancies, but efficacy is often limited by the extent of expansion and persistence of engineered lymphocytes. In a patient with a delayed clinical response, we show that a complete and durable response to CAR T cell therapy resulted from a clonal expansion of a single CAR T cell. At the peak of the antitumor response, 94 percent of CD8+ CTL019 cells originated from a single clone in which proviral insertion disrupted the gene encoding the methylcytosine dioxygenase TET2. We conclude that loss of function of TET2 secondary to insertional mutagenesis promoted T-cell proliferation, and that the progeny of a single CAR T cell induced durable remission in refractory leukemia. In solid tumors, we have observed antitumor activity in patients with ovarian cancer, pancreatic ductal adenocarcinoma, pleural mesothelioma, and glioblastoma following infusion of CAR T cells expressing scFv specific for mesothelin or EGFRvIII. However, this approach has not yet resulted in complete tumor eradication. Using genome-edited T cells, it may be possible to enhance and prolong the activity of T cells that have disrupted immune and metabolic checkpoints. In preclinical studies, we show that TCR-specific T cells have enhanced antitumor activity following disruption of TCR alpha and beta genes and the PD1 gene using CRISPR/Cas9. This approach is just entering a clinical trial. These findings provide insights into the immunobiology of effector T cells and demonstrate the potential of multiplexed CRISPR/Cas9 genome editing to synthetically enhance the efficacy of immunotherapy.

A phase II study of sorafenib (BAY 43–9006) in recurrent diffuse large B cell lymphoma: an eastern cooperative oncology group study (E1404)

Patients with diffuse large B cell lymphoma (DLBCL) who are not candidates for or recur after autologous stem cell transplant have a poor overall prognosis. We conducted a phase II study of sorafenib (formerly BAY 43–9006) in the treatment of relapsed DLBCL. Fourteen patients were enrolled and assessed for response. Median number of cycles administered was 3 (range, 1–12). Common grade 3 toxicities included fatigue (29%), rash/desquamation (21%) and diarrhea (14%). One complete response (CR) was observed (the 14th patient enrolled). Response rate was 7% (90% CI, 0.4 – 30%). Duration of response was 6 months. Median progression-free survival (PFS) was 2 months (90% CI, 1 – 5 months). Median overall survival (OS) was 9 months (90% CI, 5 – 16 months). Although sorafenib has demonstrated activity in solid malignancies it demonstrated low single agent activity in treatment of DLBCL.

A Novel Benzothiazole Derivative YLT322 Induces Apoptosis via the Mitochondrial Apoptosis Pathway In Vitro with Anti-Tumor Activity in Solid Malignancies

Benzothiazole derivatives are known for various biological activities, and their potency in cancer therapy has received considerable attention in recent years. YLT322, a novel synthesized benzothiazole derivative, exhibits potent anti-tumor activity via inducing apoptosis both in vitro and in vivo. In this study, we found that YLT322 showed growth inhibition against a broad spectrum of human cancer cells and induced apoptosis of HepG2 cells in a dose- and time-dependent manner. The occurrence of its apoptosis was associated with activation of caspases-3 and -9, but not caspase-8. YLT322 increased the expression of Bax, decreased the expression of Bcl-2, and induced the release of cytochrome c which activates the mitochondrial apoptotic pathway. The down-regulation of phosphorylated p42/44 MAPK and phosphorylated Akt was also observed. Moreover, YLT322 suppressed the growth of established tumors in xenograft models in mice without obvious side effects. Histological and immunohistochemical analyses revealed an increase in TUNEL and caspase-3-positive cells and a decrease in Ki67-positive cells upon YLT322. These results suggest that YLT322 may be a potential candidate for cancer therapy.

Gemcitabine in hematologic malignancies.

Gemcitabine is a pyrimidine analogue that showed significant activity in solid malignancies. Gemcitabine acts by inhibiting DNA synthesis through chain termination and ribonucleotide reductase inhibition. During initial phase I and II studies, gemcitabine had a low toxicity profile and was well tolerated as a single agent and in combination therapy. Recently, there has been more interest in studying the activity of gemcitabine in hematologic malignancies. Gemcitabine demonstrated good activity in refractory Hodgkin disease patients, non-Hodgkin lymphoma, cutaneous T-cell lymphoma, and acute leukemias. There is a preponderance of evidence on the activity of gemcitabine in vitro in myeloma and leukemic cell lines. The activity of gemcitabine in these disorders will pave the way for incorporating this agent into the early phases of therapy.