Pidilizumab (CT-011) is a humanized monoclonal antibody (mAb) that modulates the immune response and inhibits tumor growth and the spread of metastases. Pidilizumab binds to PD-1 (Programmed Death-1), an inhibitory receptor belonging to the B7-receptor family that is expressed on lymphocytes and myeloid cells. Mechanistically, the binding of pidilizumab to PD-1 results in the attenuation of apoptotic processed in lymphocytes, primarily effector/memory T cells. Pidilizumab also augments anti-tumor activities of NK cells. The enhanced activities of T and NK cells are translated into the intensification of anti-tumor immune response and the generation of tumor-specific memory cells. Pidilizumab is being developed as a treatment for hematological malignancies and solid tumors.
PD-1 and its ligand, PD-L1, have been demonstrated to play a central role in tumor recurrence and progression . The presence of these molecules on different tumors including different kinds of lymphoma, colorectal carcinoma, renal cell carcinoma and others, has been associated with poor prognosis and their expression was correlated with immune suppression at tumor-involved sites.
The efficacy of pidilizumab was studied in a variety of experimental tumor models for leukemia/lymphoma, melanoma, lung, colon, fibrosarcoma, breast cancer and more. In all these models, single or multiple antibody doses administered 10–14 days post tumor inoculation were able to inhibit tumor growth, to extend the survival of tumor-bearing mice, and to generate tumor-specific protection against tumor re-challenge.
A Phase I, dose escalation, clinical study in 17 hematological malignancy patients has been completed. The study showed that a single administration of CT-011 (0.2 to 6.0mg/kg) was overall safe and well tolerated with no observed serious/unexpected treatment-related adverse events and no observed infusion-related responses or autoimmune reactions. No single dose MTD could be established in this study. Interestingly, apparent clinical responses were observed in six of the patients exhibited as extended survival as follows: one Complete Remission (NHL - follicular lymphoma), four Stable Disease (HD, 2 CLL, and MM), and one minimal response (AML). Amongst immune modulating molecules, CT-011 presents a safe alternative exhibiting no signs of autoimmunity which commonly occurs in the presence of other immune-modulating antibodies.
An international Phase II program has been initiated to explore the safety and efficacy of pidilizumab in hematological malignancies and solid tumors. A Phase II in patients with diffuse large B-cell lymphoma following autologous stem cell transplantation has been successfully completed.
In this open‑label, non‑randomised, international Phase II study in 72 patients with DLBCL following autologous stem cell transplantation, pidilizumab treatment was shown to result in a progression-free survival of 72% and overall survival of 84% 18 months after transplant. Among the 27 high-risk patients who remained PET positive after salvage chemotherapy, the 18 month progression-free survival was 69%. Among the 40 patients with measurable disease after transplant, the overall response rate after pidilizumab treatment was 45%. Treatment was associated with early and persistent increases in specific subsets of circulating lymphocytes. Efficacy data compare favourably with previously reported cohorts and suggest that PD-1 blockade after autologous transplant using pidilizumab may represent a promising therapeutic strategy in this disease.
Enrolment of patients to 2 additional Phase II studies in patients with metastatic colorectal cancer and metastatic melanoma has been completed. Several other studies in different hematological and solid malignacies are ongoing.