As competition in the immuno-oncology field continues to ramp up, a number of biotech and pharma startups, as well as established companies, are leaping for the chance at a big payoff and an effective new cancer therapy attached to their name. Recently, oncology-focused firm TESARO, based in Waltham, Massachusetts, announced that it has commenced a phase 1 clinical trial for its anti-PD-1 monoclonal antibody drug known as TSR-042. The initial phase will identify doses and schedules for administering the drug, at which point the trial is expected to divide into tumor-specific groupings.
TESARO hopes to have a dose and schedule solidified by the end of 2016 so that the efficacy of the drug in different oncological indications can be examined. TSR-042 is TESARO’s first antibody candidate in its immuno-oncology portfolio to enter clinical trials, and the firm plans to introduce a second candidate from the portfolio later this year. The second candidate, TSR-022, is an anti-TIM-3 antibody therapy.
TSR-042 is the result of a collaboration between TESARO and AnaptysBio that began in March 2014 to target TIM-3, LAG-3, and PD-1, as well as two bispecific antibody drugs, one of which targets PD-1 and TIM-3 and the other targets PD-1 and LAG-3. In addition, the two companies are exploring a novel bispecific antibody that targets undisclosed proteins.
Effective Immunotherapy through Multidrug Therapies
While the announcement of clinical trials for TSR-042 is exciting, the possibility of bringing TSR-042 to the human trial phase is equally as important. Many approaches to immunotherapy have focused on immune checkpoint regulation. Through checkpoint regulation, the immune system self-regulates its attacks to ensure that it does not harm healthy cells. Unfortunately, many cancer tissues have evolved to use these same pathways to hide from immune surveillance. Many proteins such as CTLA-4 and PD-1 are involved with this process, and they are some of the most important in terms of current cancer immunotherapy. TIM-3 is another important protein that has not received as much attention, as is LAG-3. Currently, there are an estimated 50 proteins involved in the check point immune network.
TESARO and AnaptysBio’s multipronged approach to the checkpoint inhibitor issue is based on extensive research on the interaction of PD-1, TIM-3, and LAG-3 in animal models and human donor cells. The company’s researchers found that surrogate antibodies for both PD-1 and TIM-3 or LAG-3 in mice had strong and long-lasting anti-tumor activity in syngeneic models. The company has also generated potent antibodies to human PD-1, TIM-3, and LAG-3 that enhance in vitro T cell activation when used alone and in combination. The research has laid the foundation for more effective immunotherapy through the concerted blockade of several different immune checkpoints.
Other Organizations Currently Running Clinical Trials
Many organizations outside of TESARO are currently running clinical trials on checkpoint inhibitors and their efficacy when used in combination with other treatments. One of the most prominent medical research institutions is Johns Hopkins University, which is currently looking into the dosage of an anti-KIR drug administered in combination with anti-PD-1 therapies among patients with advanced refractory solid tumors, including melanoma. The phase 1 study looks to see how pairing anti-KIR, about which little is known, with anti-PD-1, a treatment approved by the United States Food & Drug Administration (FDA) for certain cancers, influences outcomes.
Another phase 1 clinical trial at Johns Hopkins looks at the effects of combining the anti-PD-1 monoclonal antibody with an anti-LAG-3. The study divides participants into three groups, one of which will receive anti-LAG-3 alone. The other two groups will receive both therapies, but one investigates patients who have previously taken anti-PD-1 or anti-PD-L1, while the other examines the effects in patients who have not had previous immunotherapy. The study is focused on advanced solid tumors.
Johns Hopkins is also looking at the role that checkpoint inhibitors can play in the treatment of other cancers, especially melanoma. One clinical program is testing the efficacy of anti-PD-1 therapies when combined with anti-CLTA-4 treatments in subjects with unresectable or metastatic melanoma who have not previously received immunotherapy treatment. A separate phase 1 study is looking at the same treatments in individuals with advanced melanoma. In addition, Johns Hopkins is currently examining the potential of a certain anti-PD-1 drug in the treatment of Merkel cell carcinoma.
Other institutions around the world are examining the potential of anti-PD-1 treatments as they work on their own or in combination with other therapies for a variety of different cancers, including non-small cell lung cancer, small cell lung cancer, hepatocellular carcinoma, urothelial cancer, and head and neck cancer.
Two PD-1 inhibitors, Opdivo and Keytruda, have already received approval from the FDA to treat a number of different cancers. Opdivo, manufactured by Bristol-Myers Squibb, is approved to treat metastatic melanoma, metastatic non-small cell lung cancer, and renal cell carcinoma. Keytruda, a Merck drug, is approved to treat melanoma and non-small cell lung cancer. With so many other drugs entering clinical trials, not to mention combinations of drugs, the coming years will prove a stimulating time for the field of immuno-oncology. As companies continue to realize success in this realm, even more will begin researching new immunotherapies.