Immunotherapy, liquid biopsy research among AACR highlights

“Driving Innovative Cancer Science to Patient Care” was the theme of the American Association for Cancer Research’s annual meeting, which took place April 14-18 in Chicago. MD Anderson faculty members joined other scientists, physicians and patient advocates from around the world to share the latest findings in translational, clinical and prevention-focused cancer research.

Here are some highlights from the meeting ...

Boosting T cells’ memory and the effectiveness of checkpoint blockade immunotherapies

Just like people, some T cells have excellent memories. These subtypes, known as memory T cells, may explain why some immunotherapies are more effective than others and could result in more effective studies using combination checkpoint blockade treatments, according to experts at MD Anderson Cancer Center.

Memory T cells are immune cells that previously have encountered cancer and gained the ability to recognize cancer antigens and reproduce more quickly, resulting in a faster and stronger defense.

The study demonstrated that combining anti-CTLA-4 and anti-PD-1 immunotherapies appears to enhance response rates and generate memory T cells in mice vaccinated with melanoma cells. The combination could explain why relapse occurs in some patients who have received treatment targeting CTLA-4 and PD-1 checkpoints, which allow cancer to evade the body’s immune system.

Findings from the study conducted in the lab of checkpoint blockade pioneer James Allison, Ph.D., chair of Immunology, were presented at the American Association for Cancer Research Annual Meeting 2018 in Chicago.

“We are learning more about the differences between anti-CTLA-4 and anti-PD-1 therapies,” said Stephen Mok, Ph.D., postdoctoral fellow of Immunology, who presented findings. “We know that while anti-PD-1 therapy has a greater response rate than anti-CTLA-4, one issue is the durability of the responses.”

Patients who receive anti-PD-1 have an average response rate of 30%, but approximately 25% of the patients experience tumor relapse within two years after treatment. Patients treated with anti-CTLA-4 have a response rate of 11% with 22% surviving at least 10 years.

The team took a closer look at memory T cells, which previous bacteria and virus studies suggest are increased by anti-CTLA-4. Conversely, anti-PD-1 tends to reduce their formation. The investigators vaccinated mice with irradiated melanoma cells and treated them with either anti-CTLA-4 or anti-PD-1 to see if there were differences in memory T cell formation.

“Although both anti-CTLA-4 and anti-PD-1 improved tumor rejection, mice treated with anti-CTLA-4 exhibited superior tumor control, suggesting the memory T-cell response by this agent is more durable,” Allison said. “In order to augment the durability of anti-PD-1 treatment, it was combined with anti-CTLA-4. What we found was that the combined treatment group had a better memory anti-tumor response compared with anti-PD-1 alone.”

The team reported that collectively their findings facilitate the design of combination immunotherapy treatments that enhance both response rates and the generation of memory T cells to prevent relapse.

“Understanding how checkpoint blockade therapies affect memory T-cell development opens up the possibilities for refining current combination immunotherapy treatments and improving patient outcomes,” Mok said.

– Ron Gilmore

Precancerous colon polyps in patients with Lynch syndrome exhibit immune activation

Colon polyps from patients with Lynch syndrome, a hereditary condition that raises the risk of colorectal cancer, display immune system activation well before cancer development, according to MD Anderson researchers. The preclinical research challenges traditional models of cancer immune activation and suggests immunotherapy may be useful for the prevention of colorectal cancer in certain high-risk groups.

Graduate research assistant Kyle Chang presented the findings, which were published in JAMA Oncology, at the American Association for Cancer Research Annual Meeting 2018 in Chicago.

Immune checkpoint inhibitors such as pembrolizumab and nivolumab that target PD-1 have been successful in treating colorectal cancers with deficiencies in DNA mismatch repair (MMR). These tumors accumulate large numbers of genetic mutations and mutant proteins, or neoantigens, which are thought to stimulate an immune response and make them more susceptible to checkpoint blockade therapy.

“Our question was how this worked in premalignancy,” said senior author Eduardo Vilar-Sanchez, M.D., Ph.D., assistant professor of Clinical Cancer Prevention and Gastrointestinal (GI) Medical Oncology. “Can we apply checkpoint inhibitors or checkpoint inhibitor strategies to prevent MMR-deficient colorectal cancer?”

Lynch syndrome (LS), which is caused by inherited mutations in MMR, provides the perfect context in which to study early immune activation and explore the potential use of checkpoint inhibitors in a prevention setting, explained Vilar-Sanchez. LS is the most common hereditary colorectal cancer syndrome, affecting more than 1 million people in the U.S.

In the study, the researchers analyzed gene expression to characterize the immune profile in 11 polyps and three early-stage tumors from 14 patients with LS. As a control, the researchers also analyzed 17 polyps from patients with Familial Adenomatous Polyposis (FAP), a hereditary colorectal cancer syndrome that does not exhibit MMR deficiencies.

The resulting profiles revealed increased expression of several markers of immune activation, including CD4 T cells, proinflammatory molecules and checkpoint molecules, such as PD-L1 and LAG-3, in LS polyps compared to FAP polyps. However, contrary to traditional models of immune activation, the observed immune profiles were independent of the rate of mutations or neoantigens present in the sample.

“To our surprise, our findings don’t follow the standard model. The majority of premalignant lesions do not have an excessive increase in mutations or neoantigens,” said Vilar-Sanchez. “However, we observed there is already immune activation, meaning the activation precedes the development of the mutations.”

The findings suggest a baseline level of immune activation exists in precancerous polyps, which may prime them for susceptibility to checkpoint blockade, explained Vilar-Sanchez.

– Clayton R. Boldt, Ph.D.

New liquid biopsy-based cancer model reveals data on deadly lung cancer

Small cell lung cancer (SCLC) accounts for 14% of all lung cancers and often quickly develops a resistance to chemotherapy, resulting in poor clinical outcomes. Treatment has changed little for decades, but an MD Anderson study offers a possible explanation for why the disease becomes chemoresistant and an avenue to explore new diagnostic approaches.

Allison Stewart, Ph.D., a research scientist in Thoracic Head and Neck Medical Oncology, presented the findings at the American Association for Cancer Research Annual Meeting 2018 in Chicago.

“There have been few therapeutic advances in the past 30 years, and platinum-based chemotherapy remains the standard of care. As a result, five-year survival is less than 7 percent across all stages,” said Lauren Byers, M.D., associate professor of Thoracic Head and Neck Medical Oncology, and the study’s principle investigator. “Most patients respond well to platinum chemotherapy initially, but relapse within a few months. There are no highly effective second-line therapies.”

The challenge in studying why and how SCLC chemoresistance occurs is due to the fact that most patients do not undergo another biopsy or surgery at the time of cancer recurrence. This leaves investigators such as Byers and Stewart with few SCLC samples with which to conduct genomic and biomarker analyses of drug-resistant tumors.

To overcome the lack of SCLC samples, the team developed novel disease models by isolating circulating tumor cells from a simple blood draw. The cells, placed under the mouse’s skin, develop tumors representative of the patient from whom they were derived. These SCLC models, called circulating tumor cell-derived xenografts (CDX), are unique to each patient and provide an opportunity to assess treatment response to novel targeted therapies, as well as changes that may occur in response to therapy.

“We hypothesize that differences in gene and protein expression between tumor cells, called intratumoral heterogeneity, contribute to the rapid development of platinum chemotherapy resistance,” Stewart said. “This means that there are likely multiple cell populations in SCLC patients who have not yet been treated. Some of those cells may be killed by chemotherapy but others will not. These resistant cells then continue to grow and prevent further response to treatment.”

Read more about this study in the MD Anderson
Newsroom.

– Ron Gilmore