Checkpoint blockade combinations

The immune system plays an important role in identifying and eliminating transformed cells via immunologic regulators known as checkpoints. Antibodies that block key checkpoints, such as the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death protein 1 pathway (PD1/PD-L1), have been developed as treatments for number of cancers.

Anti-PD1/PD-L1: The first PD1-targeted monoclonal antibody (mAb) to enter clinical trials more than 10 years ago was nivolumab. Since then, a further six antibodies targeting either PD1 or its ligand PDL1 have received FDA approval for the treatment of multiple cancer types. Recent research efforts have focused on combining anti-PD1/PDL1 agents with other therapies. A recent review of the clinical trial landscape for PD1/PD-L1 therapies, documented over 2,200 clinical trials registered, including 1,716 combination trials. Other therapies being tested in combination include chemotherapy, radiotherapy, chemoradiotherapy, anti-angiogenic agents, and other immunotherapies (see below).

• The anti-PD1 monoclonal antibody atezolizumab (Tecentriq) is currently in a series of clinical trials for indications in a range of cancers as well as in combination with other targeted therapies such as Tarceva (erlotinib), Alecensa (alectinib), and non-immunotherapy treatments.
• Following poor results in a phase III liver cancer trial last year, there will be increased interest in other trials for the immune therapeutic Keytruda. Along with further trials in liver cancer, it is also in phase III studies for cervical, breast, esophageal, gastric, ovarian, small cell lung, renal, nasopharyngeal and mesothelioma indications.

Anti-CTLA-4 therapeutics: Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), is a T cell surface marker that regulates the ability of T cells to recognize and eliminate cancer cells. Once activated, CTLA-4 downregulates T cell activity. Therefore, molecules that deactivate CTLA-4 (together known as CTLA-4 blockade) promote the ability of T cells to locate and destroy neoplastic cells. More than 300 of the registered trials for PD1/PD-L1 therapeutics combine treatment with anti-CTLA4 agents. The aim of combining treatments is to exploit the complementary mechanisms of two antibody therapies within the context of a single treatment regimen, thereby improving efficacy. The first checkpoint blockade combination to achieve FDA approval was nivolumab plus ipilimumab for use in BRAF V600 wild-type metastatic and unresectable melanoma. There are now more than 100 clinical trials investigating applications for this combination including:

• In March 2019, the NIMBUS trial is scheduled to begin and run until 2022. This phase ll trial will investigate the combination of nivolumab plus ipilimumab for efficacy in treating hypermutated HER2 negative breast cancer.
• Results and follow-up from the CheckMate 214 trial will continue into 2019. This phase lll clinical trial examined the use of nivolumab plus ipilimumab for treating advanced or metastatic renal cell carcinoma. Due to the open-label nature of this trial, concern has been expressed over the patient-reported outcomes that were incorporated in the original trial analysis. As further follow-up data become available, the use of patient-reported outcomes in trials is likely to receive further scrutiny.

CAR T-cell therapies

Chimeric Antigen Receptor (CAR) T-cell therapy involves the genetic manipulation of an individual patient’s T-cells to destroy cancer cells. The T-cells are engineered to express a CAR molecule specific for a tumor marker, grown in ex vivo cell culture, and infused into the patient. Clinical trials have shown promising results in end-stage patients with hematological cancers. The first FDA approval for CAR T-cell therapy was for the molecule Kymriah® in the treatment of pediatric and young adult patients with refractory B-cell precursor acute lymphoblastic leukemia (ALL). The compound has since been granted approval for other hematological oncology indications, which has prompted clinical trials such as:

• In March 2019, the first results from a National Cancer Institute (NCI) investigating the use of CAR T-cell therapy in B-cell lymphoma were released. This trial focusses on the efficacy of this treatment for patients with B cell lymphomas or leukemias expressing the CD19 marker. It is expected to end in 2020.

CAR T-cells therapies targeting classic hematologic markers such as CD19 have achieved remarkable results. However, it has been observed that target cellular markers may not always be present on the cell surface, a phenomenon known as antigen escape. This has been observed in ~10- 20 percent of some patient populations and has prompted the need for further research on novel hematologic markers. Clinical trials are ongoing for targeting CD138 or B-cell maturation antigen (BCMA) in multiple myeloma and CD33 and CD123 markers in acute myelogenous leukemia (AML).

The translation of CAR T-cell therapy to solid tumors is also an area of intense interest, although results have so far been limited. Within the circulatory system, infused CAR T cells can easily identify, and target transformed cells. However, solid tumors have few blood vessels at their centers and T cells are unable to reach their targets. Some interesting examples applying CAR T-cell therapies in solid tumors include:

• A phase I trial investigating the use of CAR T-cells specific for the HER2 antigen in treating glioblastoma was published in 2018, with promising results.
• An NCI phase I / II study on patients with gliomas treated with CAR T-cells specific for an EGFR variant is due for completion in 2019.

The biotech firm Cellectis has developed allogenic CAR T-cell therapies with three candidates in clinical trials. This approach employs gene editing of donor cells to render them compatible with any patient. This development could reduce the cost and delays associated with harvesting and engineering cells from individual patients.