The 2020 Annual Meeting of the American Association for Cancer Research (AACR) is now the largest cancer conference in the world, breaking attendance records with more than 47,000 people logging in to this first-ever “virtual” meeting of this size.
Combinations of more than one immunotherapy (IO) drug or combos of IO drugs with current best practice treatments (standard therapies) dominated the morning discussions, notably in one of the most prevalent cancers, breast cancer, which affects roughly two million people each year globally.
The I-SPY 2 study, a pioneering platform clinical trial designed to determine the best treatment for individual breast cancer patients, involved a combination of olaparib (Lynparza®), a small molecule inhibitor of the PARP pathway involved in DNA repair, with the anti-PD-L1 immunotherapy atezolizumab (Tecentriq®) and paclitaxel chemotherapy prior to surgery. Compared to chemotherapy alone, according to Lajos Pusztai, M.D., D.Phil., of the Yale Cancer Center, this combination improved pathologic complete response (pCR) rates in patients with stage II/III, HER2-negative breast cancer. In general, patients were more likely to have had complete responses by the time they underwent surgery if their tumors expressed high levels of immune-related markers.
With respect to the different types of HER2-negative tumors, the combination increased pCR rates from 22 to 37 percent in patients with estrogen receptor (ER)-negative tumors, from 14 to 28 percent in patients with estrogen receptor (ER)-positive tumors, and from 27 to 47 percent in patients with triple-negative breast cancer (TNBC), a particularly hard-to-treat form of the cancer that doesn’t respond to most conventional treatments.
Steven J. O'Day, M.D., of the John Wayne Cancer Institute at Providence Saint John's Health Center, discussed another PD-1/PD-L1 combination being explored in the IMPRIME 1 trial. Here, patients with metastatic, recurrent triple-negative breast cancer were treated with Imprime PGG, a yeast-derived product designed to stimulate the innate immune system, and pembrolizumab (Keytruda®). More than half of patients (54.6 percent) had disease stabilization, including 16 percent whose tumors shrank enough (>30 percent) to qualify as a partial response. Furthermore, as early as three weeks after patients began receiving therapy, blood tests showed activation of both the innate immune system and killer T cells that was associated with immune cell infiltration into tumors and was linked to longer progression-free and overall survival.
Lung cancer, which claims more lives than any other—about 1.8 million per year globally—is also being targeted with combination immunotherapy. Jie Wang, M.D., Ph.D., of the National Cancer Center/Cancer Hospital (China), spoke about the combination of camrelizumab (AiRuiKa ™), a PD-1 checkpoint immunotherapy, and the small molecule apatinib, which is designed to inhibit tumor blood vessel growth. In patients with extensive-disease small cell lung cancer (ED-SCLC), the combination led to a 34 percent response rate, compared to response rates ranging from 9 to 23 percent with standard of care topotecan (Hycamtin®) chemotherapy.
Byoung Chul Cho, M.D., Ph.D., of the Yonsei Cancer Center in South Korea, discussed another lung cancer trial—Merck’s Keynote-042—in which previously untreated patients with advanced, PD-L1-positive non-small cell lung cancer (NSCLC) were treated with either pembrolizumab (Keytruda®) or standard chemotherapy (carboplatin plus paclitaxel or pemetrexed). He focused on two genes that are often mutated in lung cancer—STK11 and KEAP1—and showed mutant versions of these genes were each associated with a trend toward higher numbers of tumor mutations, although they didn’t appear to affect patient responsiveness. Cho concluded that pembrolizumab should be considered as a first-line treatment for advanced, PD-L1-positive NSLC regardless of a patient’s mutational status with respect to these two genes.
In advanced cancers, Ryan Sullivan, M.D., of Massachusetts General Hospital, discussed efforts to inhibit a novel immune checkpoint—known as PVRIG—via the drug COM701. Alone, COM701 led to a clinical response in one of the sixteen patients treated, and to disease stabilization in another ten. Twelve patients were also treated with the combination of COM701 and nivolumab, a PD-1 checkpoint immunotherapy. Ten had disease stabilization and one, a patient with microsatellite stable (MSS) colorectal cancer, had a clinical response that was still ongoing at 44 weeks. Overall, of the 28 patients treated, six remained progression-free for at least six months.
OX40 is another molecular pathway thought to be important in immune responses. Thus, the novel nanoparticle-based immunotherapy called mRNA-2416 seeks to stimulate the OX40 pathway. After injection into tumors, the nanoparticles release their payload, which encodes the recipe for the OX40L protein that binds and activates OX40. Antonio Jimeno, M.D., of the University of Colorado Cancer Center, spoke about a trial employing this strategy in patients with several types of advanced cancers, and explained that this treatment increased T cell infiltration into tumors as well as OX40L expression. Overall, 14 of 39 patients treated with mRNA-2416 had disease stabilization, with six having durable responses of at least 14 weeks. In mice, this treatment was shown to synergize with PD-1 checkpoint immunotherapy, an approach also being evaluated in this ongoing study.
Cancer vaccines are another immunotherapy approach being investigated, including for patients with cancers associated with infection by human papilloma virus (HPV). Jung Won Woo, Ph.D., of Genexine, described GX-188E, a DNA-based, HPV-targeting vaccine that was able to induce T cell responses against HPV markers in 18 of the 23 patients evaluated in the small study. Overall, 11 of 26 patients responded, including four whose tumors were completely eliminated. All of these complete responses were observed in patients with PD-L1-positive, HPV16-positive disease, and all are currently ongoing, ranging from six to sixteen months. Partial clinical responses were also seen in patients with PD-L1-negative and HPV18-positive cancers.
In leukemia, Sergio Rutella, M.D., Ph.D., of Nottingham Trent University in England, revealed results from a study with flotetuzumab, a bispecific antibody that targets cancer cells (via the CD123 surface receptor) as well as T cells via the CD3 receptor in order to facilitate their interaction. In particular, patients with acute myeloid leukemia (AML) characterized by mutations in the TP53 gene—which encodes the tumor suppressor protein p53—were more likely to respond to this bispecific antibody. Compared to patients with normal TP53, those with mutated TP53 had higher levels of “killer” T cells and a greater expression of immune checkpoints that can suppress immune activity. Forty percent of these patients responded to flotetuzumab treatment, and their numbers of leukemic bone marrow cells decreased by an average of 42 percent.
One of the final virtual sessions of the day focused on two topics that will be necessary to understand and address if we’re going to improve care for more patients. One is the tumor microenvironment, which consists of the variety of cells, proteins, and other signals within tumors that can impact cancer growth and immune responses. The other is the microbiota, or the collection of bacteria and other microorganisms that reside in and on the human body, especially on our skin and in our intestines.
To better understand the microbiota’s impact on immunotherapy, Marcel Batten, Ph.D., presented work led by former CRI grantees Richard A. Scolyer, M.D., and Georgina V. Long, M.D, Ph.D., both of the Melanoma Institute Australia, that profiled the genomes of bacteria and other naturally occurring microscopic organisms found in fecal samples from stage III melanoma patients prior to treatment with anti-PD-1 nivolumab and ipilimumab, an anti-CTLA-4 checkpoint immunotherapy. Their team found that both those who didn’t respond as well as those who had severe side effects had low bacterial diversity. On the contrary, responses were associated certain types of bacteria—such as Ruminococcaceae and methanogenic archaea—as well as the presence of pathways involved in the production of the molecule butyrate.
With respect to the tumor environment, Athanasios Papadas, M.D., of the University of California, San Diego, characterized how a bioactive protein fragment, versikine, impacts dendritic cells, which are important immune cells that orchestrate immune responses. When versikine-expressing cancer cells were implanted into mice, they increased the numbers of dendritic cells capable of recruiting and activating the cancer-targeting T cells of our immune system. The presence of versikine also increased the effectiveness of a STING agonist—a drug that activates this important immune pathway in cancer treatment. This study was in mice, and human trials are in planning.
Follow us for our recap of the second day of #AACR20, which will feature sessions on cellular immunotherapies as well as the impact of COVID-19 with respect to cancer care.
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