How Cancer Cells Die May Affect Patient Outcomes and Which Therapies to Use in CRC

Immunogenic cell death (ICD) is a tumor cell death that involves both an innate and adaptive immune response. Prior research has found that oxaliplatin, but not irinotecan, drives ICD. However, questions remain whether single nucleotide polymorphisms (SNP) in the ICD pathways are associated with oxaliplatin-based chemotherapy efficacy in metastatic colorectal cancer (mCRC).

An analysis of the FOLFOX (folinic acid, fluorouracil, oxaliplatin)/bevacizumab (Avastin) discovery cohort in the MAVERICC trial (NCT01765582), FOLFOXIRI (folinic acid, fluorouracil, oxaliplatin, irinotecan)/bevacizumab validation cohort in the TRIBE trial (NCT00719797), and 2 control cohorts of FOLFIRI (folinic acid, fluorouracil, irinotecan)/bevacizumab in both trials examined the effects of SNPs in ICD pathways.

Overall, 648 patients were included in the analysis. For the patients receiving FOLFOX/bevacizumab, 3 SNPs—CALR rs1010222, ANXA1 rs1050305, and LRP1 rs1799986—were associated with significantly improved clinical outcomes. While statistical significance was not reached, multivariate analysis confirmed the trend. Predictive results were confirmed by the treatment-by-SNP interaction test. There were also significant associations of ANXA1 rs1050305 and LRP1 rs1799986 with clinical outcomes in patients receiving FOLFOXIRI/bevacizumab treatment. Additionally, no significant association of the 3 SNPs were observed in the 2 control cohorts.

Heinz-Josef Lenz, MD, the associate director of clinical research at the USC Norris Comprehensive Cancer Center and affiliate member of the Lawrence J. Ellison Institute for Transformative Medicine, discusses ICD and the results of using these chemotherapies and immunotherapy in an interview with Targeted Oncology.

TARGETED ONCOLOGY: What was the rationale for looking at genetic variants in immunogenic cell deaths for this study?

LENZ: For many years, my laboratory has been very interested in developing immunotherapies for patients with mCRC, particularly MSI [microsatellite instability]-high tumors. We were conducting many immunotherapy trials, including the first line trial with nivolumab [Opdivo] and ipilimumab [Yervoy] and saw significant success. So, we were asking whether potential combination with chemotherapy would potentially increase the immunogenicity of immunotherapy, and whether the combination partner with chemotherapy would matter. So, we went back to our large cohort of annotated tumor samples and asked the question: Does it matter how cancer cells die, either through oxaliplatin, or irinotecan, or if the antibodies matter, in order to increase potentially the immunogenicity of the tumor? What we found out [is] it does really matter. Oxaliplatin creates more ICD than irinotecan and cetuximab [Erbitux] tends to have more ICD than bevacizumab. So, we identified for the first time that the chemotherapy may impact combination strategies with immune checkpoint inhibitors or other immune modulators.

TARGETED ONCOLOGY: How was the study designed? What were the methods?

LENZ: Fortunately, we have access to genomic DNA data and tumor DNA data from large randomized clinical trials, from Europe as well as from the United States. So, we looked at all genes and family of genes involved in ICD, how these cells die, because when the cell dies, it may release a certain antigen and the host, the patient, who cleans up these dead cells may initiate an immune response. So, we looked at all potential candidates that could be involved in an immune genetic response after killing it with chemotherapy and identified whether there were variations of these genes. Meaning certain mutations of polymorphism, which modified the function of this genes. We put this list together and tested that in randomized clinical trials, where we could compare oxaliplatin versus irinotecan. We would conduct comparisons of cetuximab versus bevacizumab containing treatment detriments.

TARGETED ONCOLOGY: Can you please discuss the results of the analysis?

LENZ: The results indicate that when we have the activation of polymorphism in immunogenic cell genes that predict the efficacy of oxaliplatin versus irinotecan, indicating that the immune response is part of the efficacy of oxaliplatin-based regimen, but not for irinotecan. We also saw a statistical trend that cetuximab has some immunogenic response compared with bevacizumab. So, our data indicate that oxaliplatin-based combinations for mCRC may be more immunogenic than default-based regimens and that cetuximab may contribute to some of the immune response we see in this [type of] patient.

TARGETED ONCOLOGY: Why do you think that oxaliplatin-based therapies did better than irinotecan-based therapies for these patients?

LENZ: No one knows for sure the answer, but preclinical data suggest that when you treat with oxaliplatin, the cells die based on DNA damage creates different response of the immune pathways. So, we already know from preclinical and mouse models that oxaliplatin may be a more immunogenic treatment than irinotecan, which just for the first time tested that in patients in randomized clinical trials where we have a control arm with not oxaliplatin versus the oxaliplatin-containing measurements. But preclinical data suggests that the difference how the cell dies through the DNA damage process is potentially responsible for recognition by the immune cells and initiating some immune reaction.

TARGETED ONCOLOGY: What do you feel is the biggest takeaway from these findings for other physicians?

LENZ: I think the biggest is that oxaliplatin or irinotecan are not the same treatment, even based on the randomized trials. The efficacy is very similar, but the way the cancer cells die is not the same. That may have an impact on combination studies in the future, particularly when you combine immune modulator or immune checkpoint inhibitors.

TARGETED ONCOLOGY: Are there any other exciting trials or research that you're working on for these patients that you'd like to discuss?

LENZ: So, I think the immunotherapy is really to changing the paradigm for the treatment for mCRC. We have seen in 2020, for the first time, that immune checkpoint inhibitors are now being used in front line for mCRC, who are MSI high. That is a complete change on how we look at CRC in the future. Not only is it more effective, but the efficacy of this well tolerated immunotherapy is beyond any expectations we had. It can cure some patients; we have response rates reaching 70%. These patients can live a normal life.

I think the challenge for the future—that's what we are working on and very excited about—is how can we make tumors that are not MSI high and responsive to immune checkpoint inhibitors, more sensitive to immune therapies? There are different, very exciting approaches being developed by using different immune modulators in the tumor microenvironment as well as combination with anti-angiogenic drugs. These trials are ongoing. I think this immune treatment success really shed some new light into the understanding of the tumor microenvironment how these tumor cells communicate with the environment of the stromal cells, the fibroblasts, the T cells, the neuron cells. So, this is a completely new area. We're doing a deeper dive into how we can take advantage of a better understanding of this complex communication system in order to develop very successful immune therapies in combination with other target agents, which would make a tumor we would call cold into a very hot, immune responsive, tumor.

TARGETED ONCOLOGY: Are there any trials that you'd like to describe in this setting?

LENZ: So, we have a number of clinical trials ongoing with a participation population. Our most advanced device is a combination of regorafenib [Stivarga] and pembrolizumab [Keytruda] which takes the advantage of the synergism of inhibiting the angiogenic pathway with VEGF and the immune checkpoint inhibitors. Early data from Japan looked very promising. We have continued to work with this clinical trial and have enrolled over 40 patients already in this trial. I think this combination may be very promising in the future to continue. I think with the avalanche of immune targets, we have now many clinical trials using new targets in the tumor microenvironment including OX40, including new Fc-engineered CT-4 antibodies, including oncolytic viruses. I think we are really pushing aggressively forward to develop any identifying novel treatment options for this patient population.

_Reference:

_{Arai H, Xiao Y, Loupakis F, et al. Immunogenic cell death pathway polymorphisms for predicting oxaliplatin efficacy in metastatic colorectal cancer. J Immunother Cancer. 2020;8:e001714. doi:10.1136/jitc-2020-001714}