Potential Applications of Cancer Vaccines Continue to Expand in Squamous Cell Carcinoma

With growing interest in the development of therapeutic cancer vaccines and oncolytic therapies, clinical trials are needed to determine the optimal settings and patient subsets in which to incorporate such approaches, according to Omid Hamid, MD. Hamid added that, if utilized effectively, these regimens could bolster responses to immunotherapy in the metastatic setting and beyond without ensuing increases in toxicity.

“While we're bringing other types of immunotherapy into standard approaches, vaccines have reestablished themselves as an optimal therapeutic [option in] the adjuvant, neoadjuvant, and metastatic settings,” Hamid said in an interview with OncLive®. “Interestingly, we have the [phase 2 KEYNOTE-942] trial [NCT03897881] evaluating the personalized vaccine [mRNA-4157 (V940)] in the neoadjuvant/adjuvant setting for multiple solid tumors. That's unbelievable, and it's the next phase of what we're looking to do.”

In the interview with OncLive conducted at the 21st Annual International Symposium on Melanoma and Other Cutaneous Malignancies (ISM), Hamid discussed the emerging roles of cancer vaccines in squamous cell carcinoma, the cessation of the phase 3 KEYNOTE-630 trial (NCT03833167), key findings from a phase 2 study (NCT041549443) evaluating cemiplimab-rwlc (Libtayo) for cutaneous squamous cell carcinoma (CSCC), and next steps for the development of novel immune-based therapies.

Hamid is a professor of medicine at Cedars-Sinai and the director of both the Clinical Research and Immunotherapy and Melanoma Programs at The Angeles Clinic and Research Institute in Los Angeles, California.

OncLive: What are the current and potential roles of cancer vaccines in clinical practice?

Hamid: It’s very interesting that there are multiple developmental paths that are moving forward with cancer vaccines, including the vaccine candidate from IO Biotech, IO102/IO103, which is an IDO and PD-L1 vaccine that's being given along with pembrolizumab [Keytruda]. Interestingly, this is an off-the-shelf vaccine and a vaccine platform that has other targets, so we'll be looking forward to the next [steps]. This has initially shown benefit in the metastatic setting, where we have not seen a lot of benefit with vaccines. [IO102-IO103 is being evaluated] in the phase 2 [setting,] and is showing the highest complete response rates we've seen [in] metastatic melanoma [along with] high overall response rates and durability. [The question now is] can we use those vaccines in a neoadjuvant approach? [This] is being investigated.

[Consider] personalized vaccines such as the [mRNA-4157] vaccine, where we take a tissue and then pull 34 neoantigens that we're vaccinating [patients] with. This is a bespoke therapy. It is along the lines of why tumor-infiltrating lymphocyte [TIL] therapy works. Those T-cells are not only going after the tumor antigen, but with TIL [therapy] there are multi-functional T-cells that go after multiple antigens. We're looking [to see if we can employ this strategy] earlier in the treatment course.

We've already seen distant metastasis-free survival and relapse-free survival [rates that are promising with this cancer vaccine]. Hopefully, [we’ll] see more [efficacy]. However, the surgical and medical oncologists in the squamous cell carcinoma field are trying to find efficacy in the highest responsive tumors and then move them further.

The Moderna vaccine, mRNA-4157, is now being looked at as a neoadjuvant/adjuvant [treatment] in resectable lung cancer, where we found efficacy with neoadjuvant and adjuvant checkpoint inhibitors. It's also being looked at in gastric cancer where we have seen very high recurrence rates, and very low durability of benefit, and it has been looked at [in] pancreatic cancer. As we have seen the power of these [cancer vaccines] in those tumors and are moving to incorporate it into [treatment approaches for] tumors that require it—pancreatic cancer, gastric cancer, esophageal cancer, and lung cancer—this signals a return to vaccination and vaccines in the malignant sphere.

In the grand scheme of things, we've moved forward and identified 3 separate checkpoints [to target with] combinations and then triplets. Our limit is toxicity, so when we have something that shows efficacy with little to no toxicity that's how we push the power of immunotherapy forward and get greater benefits with TIL therapies in combination. Hopefully, we can add a vaccine to that.

The data monitoring committee recommended stopping the KEYNOTE-630 trial for futility. What are the implications of this decision for further development of adjuvant pembrolizumab in this patient population?

The idea here is that we cannot just take a PD-1 therapy that has worked in 1 tumor type and indicate [it] benefits the entire class of tumors just because of location. It clearly brings us to the need to continue to foster clinical trial accrual and development of paradigms. [We need to know] whether adjuvant or neoadjuvant [treatments] functionally benefit [patients] or if we should move on to other applications or therapeutics.

The fact that a single agent does not work does not rule out a possibly stronger combination providing benefit in that setting. However, it's also a call to an understanding that we need to develop other immunotherapies and other correlatives to [not only] tell us what subgroups will benefit, but also [what] other therapeutic paradigms can enhance the benefits of immunotherapy [and] not increase the toxicity of these therapies. Why do I say that? We're at a time where there's an explosion of roles for vaccines. If this approach is not efficacious, would there be the ability to increase the efficacy and then figure out a path forward with a nontoxic partner vaccination or personal cancer vaccine?

Beyond PD-1 blockade, what novel immune-based therapies are emerging in squamous cell carcinoma?

In squamous cell carcinoma, oncolytic therapies are coming to the forefront. We've talked about the Replimune RP1, RP2, and RP3 vaccination protocols that carry GM-CSF, CTLA-4, CD40, and other checkpoints. For patients with squamous cell carcinoma, where the majority [of tumors] are local, locally advanced, and metastatic, [these] make a lot of sense. Why? Systemically, we don't need a lot. Locally, we need things. The majority of our patients with CSCC are immunosuppressed and may have autoimmune disease post-transplant [to the point] where we don't want to give systemic therapy. As we build up other therapeutics in melanoma [and] skin cancers, the non-melanoma skin cancers will also benefit. We benefited [from the development of] anti–PD-1 therapy for basal cell, squamous cell, and Merkel cell [carcinomas]. As we move forward with natural killer cell therapies and other broad-based immunotherapeutics we'll see the same.

What biomarkers or clinical characteristics could guide the selection of novel agents for patients with CSCC?

CSCCs are very interesting. [We] rarely [saw patients with CSCCs] in our clinics due to a lack of therapeutics, and now they are coming back given the benefits that we've shown with checkpoint inhibitors. They respond so well [to these therapies] because they have the highest mutational load of any tumor out there. In addition, patients with CSCCs who are immunosuppressed harbor an even greater number of mutations, which indicates that they respond well to single-agent PD-1 [therapy]. Their sequencing [could] reveal other targets that we can utilize, either as monotherapy or in a combination approach.

Other targets can indicate improvements in response based on homologous recombination deficiency—mutations that respond to PARP inhibition. What we know about PARP inhibition in other solid tumors is that it can synergize with immunotherapy and radiotherapy, and those are stalwart therapies in CSCC. Therefore, what we've learned from other cancers is helping us use these therapies in CSCCs that are primary refractory or display secondary resistance.

Reference

1. Hamid O. Novel Mechanisms in Melanoma and Beyond: Emerging Agents in NMSC. Presented at: 21st Annual International Symposium on Melanoma and Other Cutaneous Malignancies; February 8, 2025.