5 Key Areas in Emerging Immunotherapy Research Stand Out

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.

“What is interesting about this study is that responses were seen not only in the lesions that were directly injected with the virus, but also in distant lesions,” Zamarin said. “It highlights that even local/ regional vaccination can result in a systemic immune response that can control the distant regions.”

When the vaccine was combined with a systemic immunotherapy in a study of T-VEC in combination with ipilimumab (Yervoy), the responses were enhanced, allowing for higher responses than could be attained with ipilimumab or T-VEC monotherapy.² The objective response rate for the combination was 50%, the progression-free survival rate at 18 months was 50%, and the OS rate at 18 months was 67%.

“If you take these two strategies targeting different parts of the immune response and put them together, you can really enhance the efficacy,” said Zamarin.

This strategy appears to be effective in patients with metastatic melanoma, and studies of this vaccine are ongoing in other tumor types. “I truly believe that with these sort of in situ therapies, we can probably find a way to benefit the majority of patients,” Zamarin stated in the interview.

However, he said more research needs to be done in order to identify the strategy that would work best for different patient populations. For instance, the intratumoral injection method used with T-VEC is limited to patients with an accessible lesion, but strategies like inhalation are being explored to deliver this vaccine to tumors within the patient’s body.

As vaccines and other methods of immunotherapy are explored in greater detail to overcome barriers such as this, immunotherapy will become more widely used across all tumor types and patients, Zamarin noted.

References

1. Andtbacka RH, Kaufman HL, Collichio F, et al. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol. 2015;33(25):2780-2788.
2. Puzanov I, Milhem MM, Minor D, et al. Talimogene laherparepvec in combination with ipilimumab in previously untreated, unresectable stage IIIB-IV melanoma. J Clin Oncol. 2016;34(22):2619-2626.