Dmitriy Zamarin, MD, PhD
Although checkpoint blockade inhibitors targeting the PD-1/PD-L1 pathway are currently dominating the oncology community’s attention, there are many other exciting approaches to anticancer immunotherapy being explored in a range of solid tumors, according to Dmitriy Zamarin, MD, PhD. As the field evolves, these less celebrated approaches to immunotherapy will increasingly make their way into treatment paradigms, Zamarin said.
Zamarin, a medical oncologist in the Gynecologic Medical Oncology Service at Memorial Sloan Kettering Cancer Center, detailed 5 categories of immunotherapy strategies currently undergoing development during a presentation at Cancer Immunotherapy 101, part of a regional series of CME-/CE accredited conferences hosted by the Society for Immunotherapy of Cancer (SITC) on August 18 in New York City (Figure)
Each step the tumor takes to resist the immune system can be prevented through one of these strategies or a combination of these approaches: anticancer vaccines, T-cell activation enhancers, regulatory T cell and macrophage-depleting antibodies, microenvironment modifiers, and direct antigen targeting. “I think immunotherapy, or some kind of immunomodulatory approach, is probably going to become a staple in every type of treatment. I think once we establish the efficacy of these drugs in the advanced setting, I can definitely envision them moving into an earlier setting,” Zamarin said in an interview with OncLive
“Ultimately, the most value we’re going to get from these drugs is not necessarily in prolonging survival of patients who already have metastatic disease, but in preventing metastatic disease from developing in the first place. That’s why I envision many such therapies moving more into the upfront setting, even prior to surgery,” he said.
Anticancer vaccines are one significant method of immunotherapy that is currently expanding. “Vaccines have had a bad reputation in cancer immunotherapy but they are making a comeback,” Zamarin said during his presentation.
Vaccines can enhance the recognition of tumor antigens by the immune system through many strategies, including DNA-encoded vaccines and virus-vectored vaccines, as well as through wholly modified tumor cells, tumor-associated antigen (TAA) or tumor-specific antigen (TSA) peptides, tumor-associated antigen proteins, dendritic cells loaded with specific antigens, adjuvants, and in situ vaccinations.
“Anything we do to a patient or their tumor to try to kill the tumor can be considered a vaccine. Any time you give surgery, radiation, chemotherapy, any sort of ablative therapy, you’re technically lysing the cancer cells and enhancing the presentation of the cells to the immune system. So in essence, we’ve been doing immunotherapy all along,” Zamarin said.
With vaccine approaches, all of the patient’s antitumor antigens that are present at the tumor site can be exploited, rather than just one specific antigen. In particular, in situ vaccination can generate localized tumor lysis and T-cell activation, as well as antigen release and presentation.
Anything that generates localized tumor lysis can be considered an in situ vaccination, according to Zamarin, even a common cancer treatment such as radiation, which has never been considered an immunotherapy.
Broadly, treatments in the in situ vaccination category include local ablative therapies (such as radiation and cryotherapy), intratumoral cytokine injections (such as interleukin-2), intratumoral tolllike receptor agonist injections, intratumoral bacteria injections, and intratumoral virus injections.
Additonally, by activating the immune response in the one location receiving radiotherapy, responses can often be seen in other lesions away from the point of vaccination, he said.
The talimogene laherparepvec (T-VEC; Imlygic) vaccine, a modified herpes simplex virus type I injected into a lesion, was first studied in patients with advanced melanoma.
The pivotal study, which compared intralesional T-VEC with subcutaneous granulocyte macrophage colony-stimulating factor (GM-CSF) therapy, found that T-VEC showed higher response rates and that patients had more durable responses to the vaccine.1
The T-VEC arm had a durable response rate of 16.3% (95% CI, 12.1-20.5) compared with 2.1% (95% CI, 0-4.5) in the GM-CSF arm (odds ratio, 8.9; P
<.001). The median overall survival (OS) for the patients treated with T-VEC was 23.3 months (95% CI, 19.5-29.6) versus 18.9 months (95% CI, 16.0-23.7) with GM-CSF (HR, 0.79; 95% CI, 0.62-1.00; P
= .051). This trial led to the FDA approval of T-VEC for the local treatment of unresectable legions in patients with recurrent melanoma in October 2015.