Panel to discuss how combination therapies could create better, longer-lasting outcomes

Jean J. Zhao, PhD
Jean J. Zhao, PhD

Targeted therapy and immunotherapy combinations are a rational attempt to overcome the deficiencies inherent in both approaches. Targeted therapies show high initial response, soon followed by increasing resistance. Immunotherapy tends to be effective in a minority of patients but has a long duration of response.

“The combination of these two approaches has the potential to result in improved and more durable outcomes,” said Jean J. Zhao, PhD, Dana-Farber Cancer Institute and Harvard Medical School. “We are seeing continuing advances with the integration of clinical and preclinical studies in translational immuno-oncology.”

Zhao will moderate the panel discussion Dharma Master Jiantai Symposium in Targeted Therapy: New Combinations of Targeted Therapies and Immunotherapies on Thursday, April 15, from 10 – 10:30 a.m. EDT. The live discussion will be based on the On Demand session of the same name. The live discussion will build off the symposium, now available as an On Demand session. Registrants can watch the symposium now and submit questions for the panel through a Q&A box available in the On Demand video.

Targeted therapy can affect immune response in some cancers, Zhao noted. In breast cancer, CDK4/6 inhibitors can overcome therapeutic resistance in HER2-positive breast cancers and also trigger anti-tumor immunity. In CT-26 colorectal tumors, combining CDK4/6 inhibition and immunotherapy leads to tumor regression.

In ovarian cancer, PARP inhibitors (PARPi) are changing the treatment landscape. Three PARPi agents have been approve as monotherapy in BRCA mutation-associated advanced ovarian cancer. But PARPi has only modest activity in BRCA-1 deficient breast cancers and no overall survival advantage over standard therapy.

BRCA-deficient ovarian cancers are rich in M1-like tumor associated macrophages (TAMs), Zhao said, while breast tumors have more M2-like TAMs. M1-like TAMs leave tumor cells sensitive to PARPi while M2-like TAMs protect tumor cells by suppressing the DNA damage associated with PARPi.

Adding a STING agonist to the regimen can reprograms M2s to an M1-like state, restoring DNA damage to tumor cells from PARPi.

Early-stage clinical trials suggest that low dose radiation can safely enhance the therapeutic outcomes of chemotherapy + immunomodulation.

George Coukos, MD, PhD
George Coukos, MD, PhD

Low-dose radiation improves T-cell infiltration and inflames cold ovarian cancer tumors in mice, said George Coukos, MD, PhD, Ludwig Cancer Research, University of Lausanne. Enhanced T-cell infiltration improves tumor sensitivity to cyclophosphamide plus immunotherapy.

A phase I trial of low-dose radiation, low-dose cyclophosphamide, ipilimumab plus nivolumab, and aspirin showed significant clinical activity in patients with multiple cancers.

“We now have evidence that low-dose radiation can be very well tolerated and inflames tumors to the point that they respond to checkpoint inhibitors,” Coukos said.

But not all preclinical models translate well.

MEK inhibition (MEKi) enhances immunotherapy in melanoma in animal models. But the combination is less effective in clinical trials because of liver toxicity, noted Siwen Hu-Lieskovan, MD, PhD, Huntsman Cancer Institute, University of Utah.

Siwen Hu-Lieskovan, MD, PhD
Siwen Hu-Lieskovan, MD, PhD

Sequencing treatment, MEKi followed by checkpoint inhibition, avoided excessive liver toxicity in phase II trials, but had only a 30 percent objective response rate. Intermittent dosing improved response in a human melanoma PDX model.

A randomized phase II trial concluded that continuous dosing of BRAF and MEK inhibition does not improve overall survival versus intermittent dosing. Triple combinations may be still more effective, but long-term data are not yet available.

Anti-angiogenesis plus immunotherapy is another possibility. Abnormal angiogenesis contributes to a hypoxic, low-pH tumor microenvironment that favors immunosuppression. An anti-VEGF tyrosine kinase inhibitor plus anti-PD1 treatment improved outcomes in advance renal cell carcinoma.

“There are hundreds of anti-VEGF/anti-PD1 trials for different tumor histologies in progress,” Hu-Lieskovan said, “Some of them in phase III. A biomarker-guided trial in advanced solid tumors will be online by the end of the year. Given the unpredictably toxicity profile of different agents in different cancers, careful clinical evaluation of each combination is prudent.”

Taha Merghoub, PhD
Taha Merghoub, PhD

Declining response and relapse rates up to 80 percent are the biggest problems with targeted therapy. Continued MEKi, for example, alters MHC expression in tumor cells to induce proliferation and survival signaling pathways in tumor cells. Continuous MEKi also interferes with T cell activation, reducing immune response.

Intermittent MEKi dosing can help, at least in mice with KRAS-mutant lung cancers.

“Pulsatile treatment with MEKi showed better tumor control and longer survival than continuous MEKi when combined with checkpoint inhibition,” said Taha Merghoub, PhD, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College. “This enhanced survival is mediated by adaptive immunity, which is favored by pulsatile MEKi. The combination of MEKi and checkpoint blockade warrants further investigation.”