Last year capped an incredible decade for cancer immunotherapy. Patients with more than a dozen types of cancer can now receive FDA-approved immunotherapies, and 2016-2017 saw the largest single-year drop in the U.S. cancer death rate ever recorded.
Despite this progress, more work remains to be done because many cancer patients still don’t respond to immunotherapy. To highlight some of the recent breakthroughs in cancer immunotherapy as well as what’s next for this promising field, we invited Padmanee Sharma, M.D., Ph.D., an immunotherapy expert at the University of Texas MD Anderson Cancer Center in Houston, TX, for the Cancer Research Institute (CRI) Cancer Immunotherapy and You educational webinar series for patients and caregivers to discuss, “Cancer Immunotherapy: 2020 Research Update and a Look Ahead.”
Currently, Dr. Sharma serves as a professor in the departments of Genitourinary Medical Oncology and Immunology, the scientific director of the Immunotherapy Platform, and the co-director of the Parker Institute for Cancer Immunotherapy (PICI) center at MD Anderson. Dr. Sharma received the 2018 William B. Coley Award for Distinguished Research in Tumor Immunology, CRI’s highest scientific honor, and is a member of both the CRI Scientific Advisory Council and the CRI Clinical Accelerator Clinical and Scientific Advisory Committee as well as a principal investigator on the CRI PORTER prostate cancer trial.
Here are some of the topics Dr. Sharma discussed during the webinar.
To kick off the webinar, Dr. Sharma highlighted two of the biggest breakthroughs from 2019—important advances in breast cancer and pancreatic cancer—as examples of what we might be able to expect in the coming year. Last year saw the first approval of an immunotherapy for breast cancer, when the combination of PD-L1 checkpoint immunotherapy and chemotherapy was approved as a first-line treatment for patients with metastatic triple-negative breast cancer (mTNBC). With respect to pancreatic cancer, a notoriously difficult type to treat, the PRINCE trial co-funded by CRI and PICI revealed impressive preliminary results in patients with metastatic pancreatic cancer who were treated with the combination of PD-1 checkpoint immunotherapy, chemotherapy, and a novel immunotherapy targeting the CD40 pathway.
HOPE AGAINST HARD-TO-TREAT CANCERS
Prostate cancer and brain cancer, especially an aggressive form known as glioblastoma, are two other types of tumors that have proven resistant to checkpoint immunotherapy, at least when it’s used alone. However, as Dr. Sharma noted, encouraging signs of progress have been seen. In prostate cancer, the CRI- and PICI-funded PORTER trial is exploring a number of novel immunotherapy combinations to tackle this disease. The adaptive design of this trial, which allows for other promising combinations to be added in the future, may also serve as a model for future clinical trials seeking to address other cancer types. In glioblastoma, Dr. Sharma pointed to recent evidence that appears to suggest that immune cells called myeloid cells may play an important role in patient responses. In the coming year, she expects that we will start to see treatments targeting these myeloid cells in combination with existing checkpoint immunotherapies that target the PD-1 and CTLA-4 pathways involved in T cell inhibition.
CUTTING-EDGE IMMUNOTHERAPY APPROACHES
Next, Dr. Sharma focused on two other immunotherapy approaches: CAR T cells and cancer vaccines. CAR T cells have already been effective in blood cancers, especially leukemia and lymphoma, but Sharma stressed that versions with additional genetic modifications—such as those in which the PD-1 “brake” has been deleted—are being tested in order to extend their benefits to solid cancers. CAR T cell therapies might also benefit from being combined with existing checkpoint immunotherapies. When it comes to vaccines, in particular those that target patient-specific mutations known as neo-antigens, they’ve proven capable of initiating immune responses against patients’ cancers. However, to achieve meaningful clinical benefit, they will likely need to be combined with other treatments in order to enable vaccine-associated immune responses to be maintained and eliminate tumors. Fortunately, these personalized vaccines have become less costly and easier to manufacture in recent years, which should enable them to be incorporated into treatment strategies more easily in the coming years.
THE POWER OF COLLABORATION
While much of the “low-hanging fruit” of immunotherapy has already been plucked for the benefit of patients, the solutions to the field’s remaining challenges will require even more intense investigation and collaboration. As Sharma said, “It's been clear that the more people you put in the room that are focusing on a problem, the better the chances are that you can come up with strategies that work… we each have our strengths that we bring to the table. And not one person is going to solve all the problems. So that's why it's important to have teams that work together.”
CRI’s Clinical Accelerator—which has been involved in the aforementioned PRINCE and PORTER clinical trials—serves as a great example of how to bring multiple stakeholders together in order to pursue a common goal against cancer.
Biomarkers are a rapidly emerging area of research in immunotherapy that stands to become more important as we learn more about them. However, there likely won’t be a single biomarker that will be applicable for all patients and cancer types. Rather, Sharma stressed, doctors will likely need to use panels of biomarkers that combine information relating to both the activity of a patient’s immune system as well as the genetic identity of their tumor, in order to enhance their ability to make the best treatment-related decisions for individual patients.
Technological advances, such as “liquid” (blood-based) biopsies and novel non-invasive imaging strategies, also have the potential to improve our ability to discover and validate new biomarkers as well as make it easier for doctors to incorporate them into standard clinical practice, although more research needs to be done to ensure their significance.
“The data are definitive,” according to Sharma, “that the microbiome is playing a role in how the immune response develops” after immunotherapy. Now, though, she said, we need a “deeper understanding of the types of microorganisms that we're talking about and then whether or not we can manipulate the microbiome.”
“How do we do that? Do we take microbiome from patients who have the good ones and transfer them to patients who don't have the good ones? Are there ways to give other therapies to manipulate the microbiome? Do we avoid things like antibiotics in certain settings so that we don't eliminate the good microbiome?”
Additionally, factors like diet and fiber intake appear to influence the microbiome, although their specific impact remains unresolved. Fortunately, a number of studies are seeking to address many of these issues, giving Sharma confidence that soon, “we'll have a sharper focus of how we can manipulate the microbiome and specific microorganisms within the microbiome to drive the clinical benefit that we're seeing with immunotherapy agents.”
Looking to the next year and beyond, Sharma pointed to the increasing importance of efforts to “develop better laboratory models to study the immune response and the tumor microenvironment.”
She also emphasized that, “we need to do a better job of what I term ‘reverse translation.’ For many years, translation consisted of looking at what happened in mice and then taking it to the clinic. Now I'm hoping, because we have over 2,000 plus immunotherapy trials ongoing—so we have a lot of patients receiving immunotherapy—that we can then take the samples from the patient… back to the lab to study the patient's immune response and the patient's tumors, so that we can design proper scientific laboratory studies based on patient data.”
Ultimately, the insights gained from those experiments would then provide promising hints about which types of approaches are most likely to work in human patients once they’re brought back to the clinic.
“I’m hoping,” Sharma concluded, “[that] these types of reverse translational studies… will be a bigger part of 2020. We've already seen some of the data coming out from that.”