Novel Approaches to Build on Checkpoint Inhibition in GI Cancers

Neeha Zaidi, MD

Despite some success stories, most gastrointestinal (GI) cancers do not respond to single-agent, or even double-agent, immune checkpoint inhibition, Neeha Zaidi, MD, said in a presentation during the 5th Annual School of Gastrointestinal Oncology™ (SOGO^®) conference.

“Novel combinatorial strategies are needed to sensitize the majority of GI cancers to checkpoint inhibition,” said Zaidi, assistant professor, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University.

Zaidi explained that a key theory on why several GI tumors do not respond to immunotherapy (ie, immunologically “cold” tumors) is because they have a low tumor mutational burden (TMB); immunologically “cold” tumors have a low number of effector T cells in the tumor microenvironment, as opposed to immunologically “hot” tumors, such as melanoma, which have greater T-cell infiltration.

“The key challenge is how do we convert these low-TMB tumors into ones that may respond to check point inhibitors,” explained Zaidi.

According to Zaidi, a multipronged, 2-step approach is required to convert “cold” tumors, which have few T cells in the tumor microenvironment, into “hot” tumors, such as melanoma, which have a higher number of effector T cells in the tumor microenvironment, and thus are more responsive to checkpoint inhibitors.

The first step is to use novel agents to induce T cells into the tumor microenvironment and/or promote antigen release. Potential classes of agents for this component include oncolytic viruses; chemotherapy and radiation; epigenetic modifiers; adoptive T-cell therapy; and vaccines. The second step to the 2-pronged approached is to use immune checkpoint agents to optimize T-cell function and quality.

“What we’re learning is it’s not only the number of T cells in the tumor microenvironment, but also the quality of these T cells,” said Zaidi, “And by quality, I mean their ability to be poly functional—to secrete multiple cytokines that can be cytotoxic. Also cells with good memory function.”

Vaccines

Vaccines are the area on which Zaidi specifically focuses in her research. There are multiple clinical trials underway exploring several vaccines strategies. Vaccines are specific to tumor cells, so they result in less off-site toxicity in normal tissue.

“The newest vaccine approach has been to target neoantigens,” said Zaidi, “We think that with a neoantigen peptide vaccine that we may be apple to get both CD4+ T cells and CD8+ T cells into the tumor but we will [likely] need to combine this with immune checkpoint inhibitors to reverse T cell exhaustion.”

Adoptive T-cell Transfer

Adoptive T-cell transfer involves, “Ex vivo expansion of tumor-infiltrating lymphocytes (TILs) that are cultured with lymphokines—for example, IL-2—and reinfused into patients, said Zaidi. “Immune cells become exhausted by the tumor microenvironment and can be reinvigorated ex vivo and reintroduced at higher doses through adoptive t-cell transfer.”

Clinical trials are also underway in GI cancers for this approach, such as NCT03190941: Administering Peripheral Blood Lymphocytes Transduced With a Murine T-Cell Receptor Recognizing the G12V Variant of Mutated RAS in HLA-A*11:01 Patients.

Another study, published in Science,¹ “Did adoptive T-cell transfer with a patient with metastatic colorectal cancer who had a pre-existing polyclonal CD8+ T cell response against KRAS^G12D.

The patient was infused with HLA-C*08-02- restricted TILs that targeted KRAS^G12D. And they did find a significant response in this 1 patient,” said Zaidi.

The patient did relapse 9 months after therapy, with 1 lesion progressing. The investigators resected the lesion and discovered that it had lost the Chr 6 haplotype that encoded the HLA-C*08:02 class I major histocompatibility complex.

Zaidi explained that thus far, a major challenge with adoptive T-cell transfer has been the “unreliability of TIL extraction and expansion.”

Epigenetic Modifiers

Epigenetic modifiers have shown promise in potentially turning “cold” tumors into “hot” tumors. The HDAC inhibitor entinostat was explored in combination with the anti-PD—1 checkpoint inhibitor pembrolizumab (Keytruda) in the open-label ENCORE 601 study.² Results showed that among 53 evaluable patients, there were 9 partial responses and 1 complete response.

An ongoing trial (NCT03250273) is exploring entinostat combined with the anti-PD—1 checkpoint inhibitor nivolumab (Opdivo) for the treatment of patients with advanced cholangiocarcinoma and pancreatic adenocarcinoma.

Zaid also stressed that there are targets on T cells being explored beyond the most common targets of PD-1, PD-L1, and CTLA-4.

One such target is CD40. A phase Ib trial is exploring the anti—CD40 monoclonal antibody APX005M in combination with gemcitabine and nab-paclitaxel (Abraxane) with or without nivolumab as a frontline regimen in patients with metastatic pancreatic ductal adenocarcinoma.

Results from the study have shown that among 30 patients enrolled, there were 14 partial responses and 8 patients with stable disease.

In her concluding remarks, Zaidi said that, “Preclinical data and early scientifically—driven clinical trials show promise for [novel combinatorial immunotherapy strategies] in GI cancers.

References

1. Tran E, Turcotte S, Gros A, et al. Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Science. 2014;344(6184):641-645. doi: 10.1126/science.1251102
2. Sullivan RJ, Moschos SJ, Johnson ML, et al. Efficacy and safety of entinostat (ENT) and pembrolizumab (PEMBRO) in patients with melanoma previously treated with anti-PD1 therapy. Presented at: 2019 AACR Annual Meeting; March 29-April 3, 2019; Atlanta, GA. Abstract CT072. doi: 10.1158/1538-7445.AM2019-CT072