DPX-Survivac/Cyclophosphamide Plus Pembrolizumab Shows Early Promise in Relapsed/Refractory DLBCL

The targeted T-cell activation therapy DPX-Survivac, coupled with low-dose cyclophosphamide in combination with pembrolizumab (Keytruda) was found to showcase promising clinical activity in patients with recurrent/refractory diffuse large B-cell lymphoma (DLBCL), according to findings from the open-label, phase 2 SPiReL trial (NCT03349450). 

The data, which were presented at the 2020 ASH Annual Meeting and Exposition, highlights the early potential with this type of therapeutic approach in oncology, explained principal investigator Neil Berinstein, MD. 

“This new immunotherapy looks promising,” said Berinstein. “Tumor reduction and disease stability with low toxicity are key for succeeding.”

In an interview with OncLive, Berinstein, who is also a hematologist at Sunnybrook Health Sciences Center, discussed the early promise with this T-cell therapy in relapsed/refractory DLBCL.

OncLive: What was the rationale to explore this T-cell therapy with pembrolizumab in this patient population? Could you highlight the mechanism of action of DPX-Survivac?

Berinstein: Recurrent/refractory DLBCL presents a major treatment challenge, especially in the setting of patients who are ineligible for, or relapsing after, potentially curative treatments such as autologous stem cell transplant (ASCT) and chimeric antigen receptor (CAR) T-cell therapy. By this point in their illness, these patients are often resistant to most standard cytotoxic treatments. Efficacious treatment options that work through novel and different mechanisms of action, that are well tolerated, and that are easily accessible in this population represent a critical unmet medical need.

DPX-Survivac is a first-in-class, T-cell–activating immunotherapy aimed at inducing a sustainable survivin-specific cytotoxic T lymphocyte (CTL) response against tumor cells expressing survivin. This immunotherapy, developed by IMV Inc., combines the company’s DPX^™ platform with the cancer antigen survivin. The DPX^™ platform is a new immunotherapy technology designed to yield robust and sustained cellular immune responses against specific targets (eg, survivin peptides).

The mechanism of action has some very unique features: when DPX-Survivac is administered, the DPX™ formulation does not release its components at the injection site, and continuously interacts with the immune system over an extended period, leading to the activation of survivin-specific cytotoxic T cells that are released into blood. The formulation has components to activate helper T-cell responses and well as cytotoxic T-cell responses. The CTLs infiltrate the tumor, recognize survivin on the surface of cancer cells, and destroy the tumor.

The protein survivin is found in more than 15 types of solid and hematologic cancers. It has been recognized as a promising tumor-associated target because it is overexpressed in a high percentage of tumor types (60% of sampled tumors in DLBCL) yet expression in normal adult tissues is limited.

Survivin is a member of the inhibitor of apoptosis protein family of proteins that are utilized by tumors to promote malignancy and evade immune detection and is involved in multiple-signaling pathways that are critical for cancer cell survival. Targeting such a critical molecule by immunotherapy makes it very difficult for cancer cells to downregulate it without extensively sacrificing their unlimited growth and resistance to standard therapies.

In preclinical studies, IMV has demonstrated that treatment with DPX-Survivac increases PD-L1 and PD-1 expression, providing the rationale for combination with pembrolizumab, a potent humanized immunoglobulin G4 monoclonal antibody with high specificity of binding to the PD‑1 receptor, thus inhibiting its interaction with PD-L1 and PD-L2.

What is the optimal patient population for this treatment? Could it be given only in PD-L1–positive patients? 

Generating antigen-specific immune and clinical responses to self-tumor–associated antigens has proven challenging. Adoptive cell transfer, such as tumor-infiltrating lymphocyte and CAR T-cell therapy have had some success, but with a notable adverse event profiles including cytokine release syndrome and neurologic toxicities. Broad accessibility for these treatments is also an ongoing challenge.

Our data set suggests that patients with PD-L1–positive disease are more likely to respond to this novel combination. We will learn more from larger studies to be conducted, but the combination of these 2 immunotherapies might be an alternative option as it is very well tolerated and could be an easily accessible off-the-shelf treatment.

Please highlight the efficacy data with this combination versus that of available therapies.

During the 2020 ASH Annual Meeting and Exposition, I described the results from the SPiReL study. In the multicenter, phase 2 SPiReL clinical trial, subjects with relapsed/refractory DLBCL were treated with DPX-Survivac, pembrolizumab and low-dose, intermittent cyclophosphamide. We highlighted that 7 of 14 evaluable patients had PD-L1 expression on their tumor cells. In the PD-L1–positive population, subjects:

• had significantly higher median progression-free survival (PFS) of 230 days, compared with the PD-L1–negative subjects (70 days) with a P value of .007, suggestive of a strong predictive biomarker for this treatment combination;
• demonstrated an objective response in 6 subjects, including 3 who have completed 1-year of study treatment;
• demonstrated an 85.7% objective response rate (ORR) and 85.7% disease control rate (DCR). 

Peripheral blood was assessed for survivin-specific, ELISpot responses in 15 subjects with available samples. All 3 subjects with a complete response, and 3 of 4 subjects with a partial response had positive ELISpot responses, while only 1 subject with stable disease and 1 subject with progressive disease demonstrated survivin-specific ELISpot response. These data suggest an association between the observed clinical responses and the mechanism of action of DPX-Survivac.

This activity compares favorably with newly approved therapies in a similar population. Those treatments demonstrate a 30% to 60% response rate but, unfortunately, half will experience high level AEs related to the therapy and about one-fourth will need to discontinue treatment due to toxicity.

How were the AEs seen in this study best managed?

This treatment combination is well-tolerated, only 11% of treatment-related AEs (TRAEs) were assessed as grade 3 or higher. The most common AEs are local grade 1/2 injection site reactions associated with DPX-Survivac administration. All reported TRAEs are in line with the expected safety profile of the combination. No subjects have discontinued study treatment due to a TRAE. 

This type of treatment is also being explored in ovarian cancer. On a broader scope, how could this type of therapy make waves in oncology?

DPX-Survivac generates a sustained and targeted cytotoxic T-cell response against cancer cells that leads to tumor regression and other clinical benefits with limited side effects. Also, this treatment is very easy to handle in the clinic. Compared with traditional immuno-oncology therapies, which require intravenous infusions and safety monitoring, DPX-Survivac is easy to administer and manage in the clinic setting and provides lesser burden on patients’ life (less office visits and safety monitoring for hematologic values).

This new type of immunotherapy is well suited for different combination regimens. The DPX-Survivac immunotherapy might be less likely to have overlapping toxicities or drug-drug interactions. 

Therefore, there are many rationally designed combination options that might be explored. The same combination treatment is currently evaluated in a basket study in several cancer indications—non–small cell lung cancer, bladder cancer, hepatocellular carcinoma, ovarian cancer, and microsatellite instability–high tumors—and IMV’s immunotherapy is being evaluated as a monotherapy in a phase 2 trial in advanced ovarian cancer. Additionally, another potential area to explore with well-tolerated immunotherapies would be maintenance settings in various tumors.

DPX-Survivac is the first of IMV’s new class of immunotherapy and the company is currently developing other cancer immunotherapies based on its versatile delivery platform DPX. 

Reference

1. Berinstein NL, Bence-Buckler I, Forward NA, et al. Clinical effectiveness of combination immunotherapy DPX-Survivac, low dose cyclophosphamide, and pembrolizumab in recurrent/refractory DLBCL: the Spirel study. Presented at: 2020 ASH Annual Meeting and Exposition; December 4-8, 2020; virtual. Abstract 2114.