Scientific summary

Since 2016, Alloplex has engaged in extensive research to refine and develop the original concept conceived by Frank Borriello, MD, PhD (U.S. Patent 10,731,128).

Alloplex has developed a non-engineered autologous PBMC-derived cellular therapy to treat cancer: based on a novel concept that relies on the scientific observation that activation of many known immune pathways elicits some degree of anti-tumor activity. Reasoning that these pathways could be harnessed into a single, cost-effective therapeutic platform, Alloplex developed a pair of engineered tumor cell lines called ENLIST training cell lines, that could simultaneously activate multiple immune pathways in PBMC to trigger an anti-tumor response.

In the process, Alloplex has identified several instances of unexpected synergistic activity in which simultaneous activation of distinct pathways was required in order to observe a strong anti-tumor response. In contrast, activation of these same pathways individually led to only limited anti-tumor activity. Thus, Alloplex created the ENLIST training cells.

These training cells serve to engage multiple activating receptors on various PBMC subsets to enhance direct anti-tumor activity. The resulting PBMC-derived trained cells are called SUPLEXA therapeutic cells and are comprised of immune cells at a heightened state of activation as determined by high level expression of adhesion molecules, chemokine receptors, activation receptors and granzymes. This array of proteins not only enable direct tumor lysis by SUPLEXA cells but also antigen presentation to host immune cells which further amplifies the host anti-tumor response.

Of note, SUPLEXA therapeutic cells differ significantly as they lack immunosuppressive cell types such as Tregs and myeloid-derived stromal cells (MDSC) that might suppress the anti-tumor response.

SUPLEXA therapeutic cells are broadly cytolytic against a variety of tumor cells but do not target normal naïve or activated immune cells, confirming that the targeting phenomenon is tumor-specific.

The emerging hypothesis is that SUPLEXA therapeutic cells mount a coordinated attack on the tumor from independent orthogonal directions which is a distinct cellular therapeutic approach from that being explored by other groups, which generally tend to rely on a specific effector cell type or target a specific tumor specific antigen. SUPLEXA therapeutic cells emerge following the simple co-incubation of ENLIST training cells with a patient’s PBMC in the absence of any additional engineering steps.

We believe that since SUPLEXA therapeutic cells are activated through naturally occurring immune receptors (already positioned to deliver physiologic strength signals), they are likely to retain natural trafficking patterns and homeostatic mechanisms which could make for a more efficacious and safe cellular therapy. The early findings of the first-in-human Phase 1 clinical trial with SUPLEXA is showing exceptional safety and tolerability and encouraging early signals

Clinical findings

  • Primary endpoint: safe profile with no drug-related serious adverse events
  • Secondary endpoint: single agent activity against multiple solid tumor types
  • Exploratory endpoint: marked pharmacodynamic immunomodulation of PBMCs

SUPLEXA shows potential as a single agent against multiple tumor cell types or in combination with any immune cell sparing therapies.

While Alloplex has opted to make our first-generation product autologous for a variety of theoretical and strategic reasons, there is potential to develop a future allogeneic administration, off-the-shelf therapy and even integrate an engineering step, should one prove to be particularly advantageous.

Manufacturing process

To render this idea commercially viable, we developed a manufacturing process capable of reproducibly yielding multiple SUPLEXA therapeutic cell doses in a simple and robust manner. This mitigates most of the liabilities historically attributed to autologous therapies; thus improving the accessibility of this new class of cellular therapy.

The manufacturing of GMP ENLIST cells – a key component – is reliable and reproducible.

  • Simple

    Manufacturing of SUPLEXA therapeutic cells using ENLIST training cells is a simple, defined process that requires neither additional genetic engineering steps, nor feeder cells. In approximately one month, the manufacturing process reliably provides for a full course of treatment from a simple blood draw.

  • Robust

    All reagents are GMP grade, resulting in a consistent product with routinely high cell yields.

  • Reproducible

    With the requirement for only standard laboratory equipment, manufacturing of SUPLEXA therapeutic cells is more readily reproducible compared with genetically engineered forms of cellular therapy.

ENLIST training cell development

Enlist Cells Development graphic

Alloplex uses proprietary engineered leukocyte stimulator cell lines (ENLIST cells) as a key manufacturing reagent to train peripheral blood mononuclear cells (PBMC). ENLIST cells are derived from a common tumor cell line to express an array of immunomodulatory ligands designed to specifically engage and activate receptors on various subsets of PBMC in a coordinated fashion.

Through a simple co-incubation step, ENLIST cells stimulate PBMCs to produce cytokines, proliferate and generate SUPLEXA therapeutic cells.

SUPLEXA therapeutic cells are comprised of a heterogeneous mixture of broadly-activated white blood cells as evidenced by their proliferation status, altered differentiation and enhanced cytokine profile. SUPLEXA cells possess a broad anti-tumor activity that appears to be independent of HLA and are tumor type agnostic suggesting that they recognize ubiquitous tumor specific motifs, possibly tumor cell stress antigens.

Research conducted to date

Pre-clinical research commenced in 2017 and concluded in 1Q, 2022. The Phase 1 first-in-human clinical trial commenced in April 2022. Here is a general guide to progress achieved in both pre-clinical and to the mid-way point of the Phase 1 first-in-human clinical trials:

Clinical trial preparation

In preparation for the Phase 1 first-in-human clinical trials, the following steps were COMPLETED as part of clinical trial preparation

  1. Establish GMP ENLIST manufacturing
  2. Independent in vitro characterization of:
    • anti-tumor activity in a patient-derived xenograph organoid model;
    • single agent single dose anti-tumor activity in a mouse xenograph model;
    • multi-dose anti-tumor activity in patient-derived xenograph model;
    • anti-tumor activity in a mouse xenograph model in a co-administration setting with cytokine support;
    • anti-tumor activity in a patient-derived xenograft model in a co-administration setting with cytokine support.
  3. GMP-SUPLEXA cell manufacturing
  4. Identification of Clinical Research Organization and initial clinical site
  5. Filing of necessary regulatory documentation in Australia and approval to proceed to in-human trial.
  6. Initiating the first-in-human clinical trial.
 

The clinical trial - which commenced in 2Q, 2022 - aims to assess the tolerability and efficacy of this differentiated approach in patients with various cancers.

Clinical research: Phase 1 first-in-human clinical trials in Australia

Steps undertaken, to date, as part of the SUPLEXA-101 Clinical trial:

  • HREC approval to start achieved.
  • First trial site open.
  • First patient enrolled.
  • Assess safety and tolerability. No drug-related SAEs to date.
  • First presentation of safety and efficacy data at SITC22.
  • Pinpoint optimal dosing. In progress.
  • Optimize GMP manufacturing. Ongoing.
  • Top line presentation of safety, tolerability and efficacy. Anticipated at SITC 2023.

Phase 1 first-in-human clinical trial

Safety risks

Alloplex characterized safety risks from an autologous therapy such as SUPLEXA therapeutic cells to be minimal, based on both preclinical animal data and on the absence of any genetically engineered receptor to deliver a supra-physiologic signal.

As an autologous therapy there is no theoretical possibility of graft vs host activity disease to negatively impact the safety profile or host vs. graft activity to negatively impact the efficacy profile. In addition, since SUPLEXA therapeutic cells are not genetically altered, there is no potential for tumorigenic mutations mediated by DNA engineering techniques.

SUPLEXA therapeutic cells exhibit

During pre-clinical phase First-in-human clinic trial
(at July 2023)
Efficacy: Broad anti-tumor activity against tumor cell lines of diverse origin, suggesting potential for efficacy against multiple tumor types in the clinic. Initial encouraging signs of outcomes across multiple tumor types have emerged in the trial to date.
Safety: The absence of cytolytic activity against normal autologous or allogeneic PBMC, as well as the absence of fratricide among SUPLEXA therapeutic cells suggests a strong clinical safety profile. Confirmed excellent safety to date. No treatment emergent SAE noted.
Tolerability: Xenografted models showed significant impact on the tumor growth with SUPLEXA treatment but no adverse impact on mouse health. Excellent tolerability. Updated protocol was well-tolerated throughout the trial with no drug-related SAEs.
Manufacturing: The low variability observed in cellular composition between SUPLEXA therapeutic cells obtained from the PBMC of normal healthy PBMC and cancer patients suggests a robust manufacturing process and reproducible product. All SUPLEXA preparations met quality requirements and specifications.

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Related independent articles (not Alloplex abstracts)

The publicly-available articles (below) establish a foundation of knowledge which may prove useful reading for scientists seeking to understand the genesis and positioning of SUPLEXA therapeutic cells.

In spite of the complex and dynamic nature of the landscape, readers will note that SUPLEXA therapeutic cells remain highly-differentiated.