Manik A. Amin, MD, on Novel Immune Therapies in GI Cancers: What’s on the Horizon?
2023 ASCO Gastrointestinal Cancers Symposium
Manik A. Amin, MD, of Dartmouth Cancer Center, discusses the future of immunotherapy in gastrointestinal cancers, the challenges of creating effective adoptive cell therapies, and the next generation of immune checkpoint inhibitors.
Disclaimer: This video transcript has not been proofread or edited and may contain errors.
Over the last few years, immunotherapy has really become a major pillar of cancer treatment. Immunotherapy is just one word, but under the umbrella of immunotherapy, we have many therapeutic targets such as immune checkpoint inhibitors, vaccine trials, adaptive cell therapies, cytokine therapies, as well as the treatments targeting the tumor microenvironment. We currently have FDA approved immune checkpoint inhibitors such as anti-PD-1, anti-PD-L1, as well as the CTLA-4 inhibitors.
Although we see durable responses with currently approved immune checkpoint inhibitors, the tumors often grow due to T cell exhaustion, decrease in the T cell effector function, and upregulation of other inhibitory immune checkpoints. Hence, we have new and exciting second-generation immune checkpoint inhibitors in development such as anti-LAG3 antibodies, anti-TIGIT antibodies, or anti-VISTA antibodies. The anti-LAG3 antibodies and anti-TIGIT antibodies are currently in phase III clinical trials, and the other co-stimulatory and inhibitory immune checkpoint inhibitors are still under early phase clinical trials and the data needs to mature for GI cancers.
When we look at the adaptive cell therapy or the personalized immunotherapy, this field has really come a long way for solid tumors, including GI cancers. The basic difference in the adaptive cell therapy is that therapy is the cells and not drugs. The goal of the adaptive cell therapy is to generate a robust anti-tumor immune response by infusion of ex vivo manipulated T cells. These T-cells could either come from the tumor, like tumor infiltrating lymphocytes, or these T cells could come from the peripheral blood of the patient or the donor. And by genetically modifying them and by infusing back into the patient, these cells can produce an anti-tumor response, such as TCR gene therapy and the CAR T therapy. We currently have clinical trials ongoing with the tumor infiltrating lymphocytes as well as TCR gene therapy and the CAR T therapy for gastrointestinal cancers.
In general. Solid tumors have a very high antigen heterogeneity, hence, to appropriately target the antigen, it's very difficult. Similarly, there could be an on target of tumor toxicity. What this means is the infused T cells are really very potent. So, along with the recognition of the antigen on the tumor, these T cells are also able to recognize the antigen expressed, even a small amount of antigen expressed, on the normal tissue and can cause toxicity in the normal tissue. Similarly, there could be some barriers to physically traveling of these infused T cells towards the tumor. Along with this, we also have toxicities from lymphodepletion regimen as well as the infusion of high dose interleukin 2.
Despite the barriers, I think there is hope because there are success stories. We recently have two case reports published in NEJM, where two patients, colon cancer and pancreatic cancer patients, were targeted with TCR gene therapy targeting the KRAS-G12D mutation. So, the field of immunotherapy is really expanding very rapidly in gastrointestinal cancer. Apart from second-generation immune checkpoint inhibitors and adaptive cell therapy or the personalized immunotherapy, there is a lot of development ongoing with vaccine trials, cytokine-based trials, bispecific antibodies, and a lot is coming.
I think the future of immunotherapy in gastrointestinal cancers is very optimistic and opportunistic. We have a lot of hope from second-generation immune checkpoint inhibitors, so stay tuned for the phase III results. Personalized immunotherapy or the adaptive cell therapies are challenging. There are barriers. However, there are successful stories of the patients being treated with this therapy, and that really brings a big hope.
Laura A. Dawson, MD, of Canada’s Princess Margaret Cancer Centre, discusses phase III findings showing that compared with best supportive care alone, single-fraction whole-liver radiation therapy appears to improve hepatic pain in the majority of patients with treatment-refractory or -ineligible hepatocellular carcinoma or liver metastases. In addition, the data indicated a trend for improved 3-month survival with radiation therapy (Abstract LBA492).
Nick Pavlakis, PhD, MBBS, of Australia’s Royal North Shore Hospital, discusses phase III findings from the INTEGRATE IIa study of regorafenib vs placebo in refractory advanced gastroesophageal cancer. The trial provides a platform for the investigation of combination therapy with an immune checkpoint inhibitor, now underway in the INTEGRATE IIb study, which is evaluating regorafenib plus nivolumab compared with standard chemotherapy in patients with this type of cancer who have received two lines of prior therapy (Abstract LBA294).
Richard S. Finn, MD, of the David Geffen School of Medicine at the University of California, Los Angeles, discusses findings from the RATIONALE-301 study, which showed that patients with unresectable hepatocellular carcinoma (HCC) treated with first-line tislelizumab had better health-related quality-of-life outcomes compared with those treated with sorafenib, particularly in terms of fatigue and physical functioning. These results, along with the effects on overall survival, response rate, and a favorable safety profile, support the benefit of tislelizumab as a potential first-line treatment option in this patient population (Abstract 495).
Laura A. Dawson, MD, of Canada’s Princess Margaret Cancer Centre, discusses phase III findings from the NRG/RTOG1112 study, which showed that stereotactic body radiation therapy (SBRT) administered prior to sorafenib vs sorafenib alone, improved outcomes in patients with advanced hepatocellular carcinoma. SBRT may become a new standard treatment option for patients with locally advanced disease, especially in the presence of macrovascular invasion (Abstract 489).
Filippo Pietrantonio, MD, of Italy’s Istituto Nazionale dei Tumori, discusses phase II results from the INFINITY trial of tremelimumab and durvalumab as neoadjuvant treatment of patients with microsatellite instability–high (MSI) resectable gastric or gastroesophageal junction adenocarcinoma (GAC/GEJAC). These results open the way to investigate nonoperative management in patients with clinical, pathologic, and molecular complete response after T300/D (300 mg of tremelimumab and 1,500 mg every 4 weeks of durvalumab) (Abstract 358).