Advancing Neoadjuvant Therapies: Oncolytic Immunotherapy and Nivolumab in MIBC

Roger Li, MD, speaks with GU Oncology Now about his recent research on oncolytic immunotherapy with nivolumab for MIBC, published in the journal Nature. For the study, Dr. Li examined the combination of oncolytic immunotherapy and immune checkpoint blockade for treating bladder cancer. This innovative neoadjuvant regimen targets micrometastatic disease in patients with both non-muscle invasive and muscle-invasive bladder cancer, showing efficacy on par with cisplatin-based chemotherapy. Dr. Li discusses the role of key biomarkers, including tumor mutational burden and E2F activity, in predicting treatment response. He also explores surprising findings regarding PD-L1 status, revealing its unexpected implications for immune checkpoint therapy. The discussion highlights the significance of tertiary lymphoid structures and their potential to enhance humoral anti-tumor response.

Transcript 

What was the rationale for undertaking this trial?

Roger Li, MD: The oncolytic immunotherapy or [inaudible 00:00:18] imaging has been tested as a monotherapy in the past in patients with non-muscle invasive bladder cancer, who were either refractory or unresponsive to BCG, and has proven to have efficacy in that setting. And we hypothesized that when combined together with immune checkpoint blockade, the combination can achieve synergistic efficacy, both in the non-muscle invasive and the muscle invasive setting.

So this study really was looking at a cohort of patients who are in dire need for systemic treatment in the neoadjuvant setting to eliminate their micrometastatic disease and, hence, the rationale for applying this regimen in that cohort population to increase the treatment benefit and also to increase recurrence-free survival.

The study reported a 42.1% pathological complete response rate with the combination therapy. How does this compare to existing neoadjuvant treatments for cisplatin-ineligible MIBC patients, and what factors might contribute to this efficacy?

Dr. Li: So as reported out originally in SWOG 8710, the pathologic complete response rate to cisplatin-based neoadjuvant chemotherapy was just around 40%. So let’s say that the pathologic complete response rates that we saw with this regimen compared equally with or on par with that that was achieved with neoadjuvant chemotherapy.

As far as the factors that could’ve contributed to the efficacy, we certainly looked at different biomarkers from the baseline tumor samples and saw that there were biomarkers indicative for pathologic complete response, including whether or not at baseline the tumors had a high tumor mutational burden, whether the tumors were expressive of E2F targets. And interestingly, there wasn’t any correlation with baseline PD-L1 level, which was seen previously in some other neoadjuvant immune checkpoint trials.

No dose-limiting toxicities were observed in the trial. Can you discuss the safety profile of this combination therapy and any notable adverse events encountered during the study?

Dr. Li: I would say that that was a strength of our study in which the neoadjuvant regimen was really given in a very short time interval. Only six weeks of treatment was required.

And because of the intravesical therapy, most of the patients experienced some bladder-related symptoms like dysuria and frequency and urgency, but there wasn’t any synergistic immune-related adverse events that were observed while on treatment given the two agents. And there wasn’t any delays to radical cystectomy, which is also a very important measure for any neoadjuvant treatment in this setting.

So I would say overall it was a very well-tolerated regimen, and especially in this patient population who have a lot of comorbidities, it’s a very promising regimen in terms of its toxicity profile.

The formation and maturation of tertiary lymphoid structures were associated with complete responses. Can you elaborate on the role these structures play in the immune response against bladder cancer and how they might inform future immunotherapeutic strategies?

Dr. Li: So tertiary lymphoid structures are ectopic lymphoid organs that have been described in chronic inflammation originally, and what these structures are is a conglomeration of B and T cells together that are existent in the tumor microenvironment indicative of a long-term inflammation. Specifically in cancer, tertiary lymphoid structures have already been described in the past to confer positive prognostic implication for multiple different cancer types, and they’ve also been linked to increased response to immune checkpoint blockade more recently.

So in bladder cancer, we’ve also looked at these structures in the past and linked them to overall better prognosis. And also in the clinical trial IMvigor 210, we’re able to link a gene signature that is associated with the presence of tertiary lymphoid structures to better response to immune checkpoint blockade in that setting. So all of this kind of brings us to the findings of this trial where we actually found that there was induction of tertiary lymphoid structures after the combination treatment.

It’s also thought that they can undergo somatic hypermutation and affinity maturation so that they can produce antibodies that are directed against their cognate antigens. And while we still are trying to uncover the nature of the cognate antigen of these B cells that are maturing through treatment, we think it could be one of two possibilities. Number one, it could be targeted against the viral particles that may be taken up by the cancer cells. And number two, it can be targeted against cancer-associated antigens themselves.

We’ve actually uncovered some evidence for this by looking at samples from a partial responder at the post-treatment biopsy time point, and we have actually seen staining of RGG on the residual tumor cells in this transient responder.

So we’re very excited about the prospects of this and uncovering some of the benefits of humoral anti-tumor response and look forward to further elucidating the nature of the cognate antigen for these B cells and how to generate more effectively these tertiary lymphoid structures so that we can confer a more clinical benefit for these patients.

Pathologic response was linked to baseline free E2F activity and tumor mutational burden but not PD-L1 status. How might these biomarkers influence patient selection and the development of personalized treatment approaches in MIBC?

Dr. Li: So certainly the link between treatment response and the tumor mutational burden has been described in other neo-adjuvant immune checkpoint blockade trials before so we’re just recapitulating the results there.

In terms of E2F activity, that really speaks to the mechanism of action of the oncolytic virus. So the virus has an E2F promoter and requires free E2F to be available for viral replication. So the free E2F activity at baseline speaks to these tumors that at baseline exhibit free E2F activity and thus can power viral replication and, hence, the oncolysis that’s required and the immunogenesis that’s required as well.

The PD-L1 status was interesting. So from previous trials, even though there wasn’t a statistically significant link, I would say that for the most part in most bladder cancer-related trials, PD-L1 has been linked to response to immune checkpoint blockade. And the fact that we didn’t observe any linkage, in fact, there was a numerically higher pathologic complete response rate in the PD-L1 negative patients than the positive patients, we take that to show that there was an effect, immunogenic effect from the oncolytic virus itself.

So in other words, you give the oncolytic virus, the virus itself can generate an immune-hot environment, upon which the immune checkpoint blockade can then reinforce the activity, thus generating tumor elimination.

So I think together all of these biomarkers point to the mechanism of action of the oncolytic virus again, and especially for those patients that would typically not respond to immune checkpoint alone, I think oncolytic virus can be added as an adjunctive treatment.