Dr Leidner on the DPV-001 Vaccine Plus PD-1 Inhibition in Metastatic HNSCC

Rom S. Leidner, MD, medical oncologist, Providence Cancer Institute Franz Clinic, member, Earle A. Chiles Research Institute, Providence Health, discusses the background for investigating the multivalent vaccine DPV-001 in combination with PD-1 inhibition with or without a GITR agonist in patients with advanced or metastatic head and neck squamous cell carcinoma (HNSCC).

Notably, this combination was evaluated in the phase 1 GITRVax trial (NCT04470024), findings from which were presented at the 2024 AACR Annual Meeting. Leidner begins by stating that he and other co-investigators developed the multivalent autophagosomal vaccine in-house. This vaccine is groundbreaking because it challenges a longstanding paradigm in tumor immunology that has persisted for over 50 years, leading to new insights into cancer’s “dark matter,” he explains.

One of the first findings that stood out in the GITRVax trial was the vaccine’s bioactivity, he continues. In both arms of the study, investigators observed early signals of immune bioactivity, coupled with a greater breadth and frequency of immune-related adverseeffects than typically seen with PD-1 blockade alone in patients with HNSCC, according to Leidner. These immune responses were soon followed by corroborative clinical outcomes, underscoring the critical importance of linking bioactivity with clinical efficacy, Leidner reports.

This connection between bioactivity and clinical response is essential, as most researchers now believe that successful combinatorial strategies with immunotherapy will likely involve some level of toxicity, which, although manageable, serves as a necessary indicator of treatment effectiveness, he says. Without such bioactive readouts, there is growing skepticism about the potential success of these therapies, Leidner says. The observed immune bioactivity in trials with DPV-001 validates the vaccine’s therapeutic potential and highlights the importance of these signals in advancing immunotherapy strategies, he notes. This work opens new avenues for understanding and exploiting the complex mechanisms underlying tumor immunity, offering hope for more effective cancer treatments in the future, Leidner concludes.

Videos

Rom S. Leidner, MD, discusses the rationale for studying DPV-001 plus PD-1 inhibition in advanced or metastatic head and neck squamous cell carcinoma.

Dr Leidner on the Multivalent Vaccine DPV-001 in Advanced or Metastatic HNSCC

Rom S. Leidner, MD, medical oncologist, Providence Cancer Institute Franz Clinic, member, Earle A. Chiles Research Institute, Providence Health, discusses data from the phase 1 GITRVax trial (NCT04470024) evaluating the multivalent vaccine DPV-001 in combination with PD-1 inhibition with or without a GITR agonist in patients with advanced or metastatic head and neck squamous cell carcinoma (HNSCC).

DPV-001 is a novel microvesicle vaccine containing proteins for genes commonly overexpressed by cancer. It is enriched with short-lived proteins and defective ribosomal products, representing potential shared non-mutated alternative cancer neoantigens, which are also referred to as cancer’s dark matter. Preclinical studies showed increased therapeutic efficacy when DPV-001 was combined with anti–PD-1 and anti-GITR therapies, informing the rationale for this clinical trial.

In the study, 18 patients received DPV-001 with sequenced a novel PD-1 therapy, INCMGA00012. Nine of these patients also received the GITR agonist INCAGN01876 starting on day 1. The study included 9 patients who were naive to prior PD-1 therapy and 9 patients exposed to prior PD-1 therapy.

Leidner notes that the overall response rate (ORR) for patients with PD-1–naive disease was 55.5% (n = 5/9), and the ORR was 33.3% (n = 3/9) for patients previously treated with PD-1 therapy patients.

Notably, 2 of the responses in the PD-1–pretreated population were with DPV-001 and PD-1 therapy alone, pointing to the activity of DPV-001, Leidner explains. Additionally, 1 of the responders in the PD-1–refractory population also had a PD-L1 combined positive score of 0, and this patient had also previously received pembrolizumab (Keytruda) in combination with lenvatinib (Lenvima), as well as an HPV16 vaccine, Leidner continues. Two of the responses in the PD-1–exposed population were ongoing, he adds, noting that this includes patients who were HPV negative.

Although the patient population enrolled on the study was small, Leidner concludes that these early data are encouraging for a difficult-to-treat malignancy.

Rom S. Leidner, MD, discusses data for DPV-001 combined with PD-1inhibition with or without a GITR agonist  in advanced or metastatic HNSCC.

Dr Leidner on the Investigation of TCR-Engineered T-Cell Immunotherapy in Solid Tumorsesponses to immunotherapy.

Dr Leidner on the Investigation of TCR-Engineered T-Cell Immunotherapy in Solid Tumors

Rom S. Leidner, MD, medical oncologist, Providence Cancer Institute Franz Clinic; member, Earle A. Chiles Research Institute, Providence Health, discusses the rationale for assessing neoantigen-targeted, T-cell receptor (TCR)–engineered T-cell immunotherapy in select patients with solid tumors, as presented at the Frontiers in Cancer Immunotherapy 2024 Symposium.

In 2016, 2 key TCRs were identified from a patient with colon adenocarcinoma and lung metastases who had received standard tumor-infiltrating lymphocyte therapy and remained alive, demonstrating a significant clinical response. This patient had TCRs specific to the 

 G12D driver mutation. One TCR targeted a 9-mer peptide overlapping with G12D, and the other targeted a 10-mer peptide. Notably, the 9-mer peptide was CD8 co-receptor–independent, allowing it to be transduced into both CD4-positive and CD8-positive T cells for potential use in other patients. Conversely, the 10-mer peptide was CD8 co-receptor–dependent, necessitating sorting for CD8-positive T cells only.

This clinical success served as proof of concept that targeting a driver mutation in cancer could eradicate the tumor. Building on this success, researchers then explored whether the 

 G12D mutation, which is common across various cancers and crucial for cancer cell growth and persistence, could be targeted in other tumors. This approach involved retrovirally transducing the identified TCR into T cells from other cancer patients. However, a key caveat for this process was that patients were required to share the HLA-C*08:02 type, which restricts the targeted 

At the Frontiers in Cancer Immunotherapy 2024 Symposium, Leidner presented 2 case studies from patients with pancreatic cancer who were treated with these TCRs. Both patients had TCRs retrovirally transduced into their own T cells that were obtained through leukapheresis. Out of the 2 patients, 1 responded to the treatment. The presentation focused on comparing and contrasting the characteristics and responses of these 2 patients, offering insights into the factors influencing the effectiveness of TCR therapy targeting 

Rom S. Leidner, MD, discusses the investigation of T-cell receptor–engineered T-cell immunotherapy for select patients with solid tumors.

Rom S. Leidner, MD

Articles

Dr Leidner on the DPV-001 Vaccine Plus PD-1 Inhibition in Metastatic HNSCC

Dr Leidner on the Multivalent Vaccine DPV-001 in Advanced or Metastatic HNSCC

Dr Leidner on the Investigation of TCR-Engineered T-Cell Immunotherapy in Solid Tumors