What PRAME modulators are in clinical trials currently?

Introduction to PRAME

Definition and Biological Role
PRAME stands for Preferentially Expressed Antigen in Melanoma and is classified as a cancer testis antigen (CTA). It is normally expressed in the testis and at very low levels in most somatic tissues, but it becomes aberrantly expressed in many malignancies such as melanoma, ovarian cancer, non-small cell lung cancer (NSCLC), endometrial cancer, and others. The biological functions of PRAME are multifaceted. Although its precise physiological role has not been fully elucidated, evidence shows that PRAME is involved in key cellular processes including cell proliferation, apoptosis, differentiation, and metastasis. Importantly, PRAME has been shown to repress retinoic acid receptor (RAR) signaling by binding to RARs, thereby antagonizing the differentiation and pro-apoptotic signals induced by retinoic acid. This dual role—as both a regulator of intrinsic tumor cell survival pathways and as an immunogenic antigen—has rendered PRAME an attractive target for therapeutic interventions.

Importance in Cancer Therapy
PRAME’s restricted expression in normal tissues and its high prevalence in various tumors offer a unique window for targeted cancer therapy. Given that its expression is relatively absent in most somatic cells, treatments aimed at PRAME have a lower risk of on-target off-tumor toxicities. The antigen is being actively pursued as a target for adoptive cell therapy, cancer vaccines, T cell receptor (TCR)-based therapeutics, and bispecific modalities to harness the body's immune system. Moreover, the high copy number of PRAME peptides per tumor cell and their homogenous expression in tumor tissues further support the rationale for its exploitation as a diagnostic marker and a therapeutic target. Overall, PRAME modulation promises a dual benefit: disrupting tumor cell survival signals while simultaneously sensitizing malignant cells to immune-mediated attack.

Current PRAME Modulators

List of Known Modulators
Several PRAME modulators are currently under clinical investigation. The most prominent examples include:

• ACTengine® IMA203: This candidate represents an adoptive T cell therapy where autologous T cells are engineered to express a high-affinity T cell receptor (TCR) targeting an HLA-A*02-presented peptide derived from PRAME. Extensive clinical data in Phase 1a and Phase 1b trials have demonstrated objective responses in various solid tumors, including melanoma, ovarian cancer, uveal melanoma, and head and neck cancer.

• TCER® IMA402: This is a next-generation TCR bispecific modality combining a TCR with an anti-CD3 effector arm. IMA402 is designed to target the same PRAME peptide-HLA complex and mediate engagement between tumor cells and T cells. The candidate is being evaluated in a Phase 1/2 clinical trial, with expansion arms currently recruiting patients with cutaneous melanoma, ovarian, NSCLC, and endometrial cancers.

• IMC-F106C: Another approach in the PRAME modulator portfolio involves this bispecific ImmTAC molecule, which leverages the ImmTAC® technology. IMC-F106C is engineered to redirect T cells to PRAME-expressing tumor cells and is being evaluated in early-phase clinical trials (with anticipated progression to Phase 3 in certain indications such as cutaneous melanoma under clinical trial PRISM-MEL-301).

These modulators, although distinct in their molecular architectures—ranging from adoptive TCR-T cell therapies to bispecific TCR platforms—share the common goal of targeting the PRAME antigen to elicit potent anti-tumor responses.

Mechanism of Action
The modalities in development work through different yet complementary mechanisms to harness the immune system:

• ACTengine® IMA203 employs autologous T cells that are genetically modified to express a high-affinity TCR specific for the PRAME peptide presented by an HLA-A*02 molecule. Upon infusion, these engineered T cells recognize and kill tumor cells expressing PRAME. This therapy not only works by direct cytolysis of tumor cells but also by altering the tumor microenvironment to favor an anti-tumor immune response.

• TCER® IMA402 functions through a bispecific mechanism, bridging tumor cells and T cells. The molecule contains two binding domains: one domain recognizes the PRAME peptide-HLA complex on tumor cells, and the other binds CD3 on T cells. Through this dual engagement, TCER® IMA402 facilitates the formation of an immunological synapse, triggering T cell activation and subsequent tumor cell lysis. The design of the bispecific molecule also incorporates a half-life extension feature, contributing to prolonged systemic exposure and dosing flexibility.

• IMC-F106C, as an ImmTAC bispecific molecule, combines a soluble, high-affinity TCR with an effector domain, typically an anti-CD3 antibody fragment. When administered, it binds with high specificity to PRAME-positive tumor cells presenting the target peptide in the context of HLA-A*02, and it simultaneously recruits T cells for target cell killing. This modality is designed to overcome issues like T cell exhaustion and tumor escape mechanisms by providing a robust link between immune effector cells and tumor cells.

These distinct mechanisms amplify immune system recognition of PRAME-expressing cells, often resulting in both direct cytotoxic effects and modulation of the tumor microenvironment to enhance the overall efficacy of the treatment.

Clinical Trials Overview

Phases of Clinical Trials
The clinical development pathway for PRAME modulators is structured into multiple phases:

• Phase 1: Early-phase trials primarily aim to evaluate safety, tolerability, pharmacokinetics, and initial signs of efficacy in a limited number of patients. Dose-escalation studies are a critical component in this phase to determine the maximum tolerated dose, as seen in the Phase 1a/1b trials for IMA203 and IMC-F106C.

• Phase 1/2: In many modern clinical paradigms, early safety evaluations and preliminary efficacy investigations are combined into adaptive Phase 1/2 studies. For instance, TCER® IMA402 is being evaluated in such a design, which allows for dose expansion cohorts that assess efficacy signals concurrently with safety.

• Phase 3: These pivotal trials involve larger patient populations and aim to confirm efficacy, further establish safety, and potentially result in regulatory approval. Although many PRAME modulators are still in early phases, plans have been announced for registrational Phase 3 trials—for example, the PRISM-MEL-301 trial for IMC-F106C in cutaneous melanoma.

Each phase is carefully designed, with critical endpoints being assessment of overall survival, objective response rates, durable responses, and biomarkers such as circulating tumor DNA (ctDNA) reductions.

PRAME Modulators in Different Phases
Detailed analyses of the PRAME modulators currently in clinical trials reveal the following status:

• ACTengine® IMA203:
– It is currently in Phase 1a and Phase 1b, with investigations focused on dose escalations and expansion cohorts. Early clinical data have shown promising confirmed objective response rates (cORR) of up to 80% in the Phase 1b expansion cohort alone. The clinical trials involve a heterogeneous patient population with PRAME-positive solid tumors, including melanoma and ovarian cancer. Extensive monitoring of tolerability and safety (with no significant high-grade cytokine release syndrome (CRS) or neurotoxicity) has been reported.

• TCER® IMA402:
– This TCR bispecific modulator is in an adaptive Phase 1/2 clinical trial stage involving multiple tumor indications. The study objectives include establishing the recommended dose, safety profiles, and additional efficacy endpoints such as tumor shrinkage and changes in ctDNA. Expansion cohorts are set up for specific cancers like cutaneous melanoma, ovarian, NSCLC, and endometrial cancers, which attest to its broad potential patient applicability.

• IMC-F106C:
– IMC-F106C, operating on the ImmTAC platform, has advanced into early-phase trials and also has plans for a subsequent registrational Phase 3 trial. Preliminary analyses indicate durable partial responses in several cancer patients, including those with cutaneous melanoma. Early data from combined Phase 1a/1b analyses show objective response rates exceeding 50%, with ongoing responses observed at data cutoffs. Robust pharmacokinetic profiles and manageable safety data support its continued clinical development.

The multi-indication approach and the adaptive trial designs currently implemented for these modulators are significant; they provide an opportunity to assess efficacy across different solid tumor types while maintaining rigorous safety standards.

Efficacy and Safety Data

Preliminary Results
Preliminary efficacy data from early-phase clinical trials of PRAME modulators have been encouraging across various studies and provide support for further clinical development:

• For ACTengine® IMA203, initial Phase 1a/1b studies have demonstrated high objective response rates in heavily pretreated patient populations. For instance, one report noted a cORR of around 50% at target cell doses, with some cohorts (specifically Phase 1b) showing an impressive 80% confirmed response rate. These responses have been maintained across multiple tumor types, suggesting broad activity of the modulated T cells against PRAME-expressing tumors.

• TCER® IMA402 has shown early signs of clinical anti-tumor activity. In patients treated at higher dose levels, tumor shrinkage has been observed in approximately 78% of evaluable patients within certain subgroups. In addition, pharmacokinetic data for IMA402 indicate a median half-life of about seven days, a feature that may support bi-weekly dosing and advantageous exposure, implying that the molecule can sustain effective concentrations over the dosing interval.

• IMC-F106C has also yielded promising efficacy data. Early-phase results from its trials demonstrated partial responses in a range of tumor indications, and the responses observed appear to be durable. Moreover, reductions in ctDNA levels suggest that the therapeutic not only induces tumor shrinkage but may also be associated with meaningful biomarker changes that correlate with clinical outcomes.

Taken together, these preliminary results support the therapeutic potential of PRAME modulators and their ability to induce anti-cancer immune responses in patients who have exhausted other treatment options.

Safety Profiles
Safety is a paramount concern in early-phase clinical trials, especially for innovative immunotherapeutic modalities such as PRAME modulators:

• In the trials involving ACTengine® IMA203, the safety data have been reassuring. The reported adverse events typically included cytopenia due to lymphodepletion, which is expected in T cell therapies, as well as low to moderate cytokine release syndrome (CRS). Importantly, no high-grade CRS or immune effector cell-associated neurotoxicity syndrome (ICANS) has been observed, indicating that the therapy is well managed from a safety perspective.

• TCER® IMA402 has also shown a manageable tolerability profile. The majority of treatment-related adverse events have been mild to moderate, with step dosing strategies further mitigating potential adverse effects. The favorable pharmacokinetic profile, including a median half-life of approximately seven days, suggests that the adverse events can be closely monitored and managed in a clinical setting.

• Similarly, IMC-F106C has exhibited a safety profile characterized by predictable and manageable adverse events. Early-phase trials indicate that while there is some treatment-related toxicity, the events are transient and within acceptable limits. This safety profile supports its progression into larger and more confirmatory trial phases.

Safety monitoring in these trials involves detailed assessments and is supported by robust dose escalation designs, which ensure that any emerging toxicities are detected early and dose adjustments are made promptly.

Future Prospects

Challenges in PRAME Modulation
Despite the promising clinical trial results, several challenges remain in the development and optimization of PRAME modulators:

• Antigen Heterogeneity: Although PRAME is commonly expressed in various cancers, its expression levels can vary among tumor types and even within the same tumor. This variability can affect the efficacy of PRAME modulators and may require sophisticated patient selection strategies using biomarkers to identify those who would most likely benefit from the therapy.

• Immune Escape Mechanisms: Like other targeted immunotherapies, PRAME modulators might encounter tumor escape mechanisms, such as downregulation of antigen presentation or mutations in the HLA system, which could diminish their efficacy over time. Overcoming these mechanisms will be critical to sustaining long-term responses.

• Safety and Off-Target Effects: Although initial safety data are promising, the long-term effects of immune activation—especially in adoptive cell therapy—need continuous monitoring. There is a risk of autoimmune side effects or on-target off-tumor toxicities when T cells are redirected against antigens that have low levels of expression in normal tissues.

• Manufacturing and Scalability: Adoptive cell therapies such as ACTengine® IMA203 require complex manufacturing processes. Although current reports indicate a high success rate (with manufacturing times as short as seven days and success rates around 94%), scaling such processes for broader clinical use remains challenging.

• Optimizing Dosing Strategies: The dosing parameters, including cell dose for ACT cell therapies and dose levels for bispecific modalities, are still being refined. The balance between achieving sufficient anti-tumor activity and minimizing toxicities requires further investigation through adaptive trial designs.

Potential Future Developments
The future of PRAME modulation appears promising, driven by both technological advancements and an increasing understanding of tumor immunology:

• Combination Therapy Approaches: One potential avenue is the combination of PRAME modulators with other immunotherapeutics such as immune checkpoint inhibitors. By relieving T cell exhaustion and modulating the tumor microenvironment, combination regimens may achieve synergistic effects, resulting in improved clinical outcomes. In fact, some trials are already exploring combination strategies, such as pairing ACTengine® IMA203 with checkpoint inhibitors to further enhance responses.

• Next-Generation Engineering: For adoptive cell therapy candidates like IMA203, next-generation engineering approaches are being developed to augment T cell persistence, enhance tumor infiltration, and improve overall potency. The development of IMA203CD8, where T cells are co-transduced with a CD8 co-receptor, represents an innovative effort that could extend the range of tumors amenable to treatment by improving the function of T cell products in medium PRAME-expressing tumors such as ovarian and endometrial cancers.

• Refinement of Bispecific Modalities: On the bispecific front, further optimization of molecular formats—such as the half-life extended design seen in TCER® IMA402—is anticipated to yield compounds with improved pharmacokinetics and enhanced safety profiles. As clinical data mature, these improvements may facilitate applying bispecific TCR-based modalities in earlier lines of treatment, potentially even in less heavily pretreated patients.

• Biomarker-Driven Patient Selection: Incorporating robust biomarker analyses, including quantification of PRAME expression, HLA typing, and ctDNA measurement, can refine patient selection. This precision approach not only enhances the likelihood of response but also mitigates the risks of adverse effects. Future trials are likely to integrate such biomarker strategies to personalize PRAME-directed therapies.

• Regulatory and Commercial Milestones: As these modalities transition into later clinical trial phases, the generation of compelling Phase 3 efficacy and safety data will be crucial for regulatory approval. Furthermore, discussions around manufacturing scalability, cost-effectiveness, and integration into routine clinical practice will shape the market adoption of these therapies. With some candidates already showing early signs of durable responses and favorable safety profiles, there is significant potential for accelerated regulatory pathways, as evidenced by planned Phase 3 trials such as PRISM-MEL-301 for IMC-F106C.

• Integration into Multidisciplinary Oncology Care: Future developments may also include the integration of PRAME modulators into the broader context of cancer treatment. This could involve not only combination with other immunotherapeutic agents but also with more conventional modalities like chemotherapy or radiotherapy. Emerging evidence suggests that modulating the tumor microenvironment—such as targeting macrophages in combination with radiotherapy—might further enhance the efficacy of targeted agents, including those directed at PRAME.

Conclusion

In summary, PRAME modulators currently in clinical trials represent a multifaceted and innovative approach to tackling several hard-to-treat cancers. The field is broadly characterized by three main therapeutic candidates actively under clinical evaluation: ACTengine® IMA203, TCER® IMA402, and IMC-F106C. Each of these modalities exploits different molecular and cellular engineering strategies to target the PRAME antigen, whose aberrant expression in various solid tumors makes it an attractive candidate for immunotherapy.

ACTengine® IMA203 utilizes autologous T cell modification to generate potent anti-tumor responses, demonstrating high objective response rates in early-phase trials across diverse tumor types with a manageable safety profile. TCER® IMA402, a next-generation TCR bispecific molecule, strategically bridges tumor cells with T cells, offering promising pharmacokinetic attributes and appealing clinical activity across multiple indications. IMC-F106C, developed on the ImmTAC platform, is similarly designed to engage and activate T cells against PRAME-positive cells and is progressing through early-phase studies with plans for later clinical evaluation in a registrational Phase 3 trial.

Safety data so far across these candidates are encouraging, with reports of low-grade cytokine release syndrome and manageable adverse events, which underscore the promise of these therapies while highlighting the need for continuous monitoring and dose optimization. The integration of these modulators into adaptive and biomarker-driven clinical trials further augments their potential as precision therapies for cancers that are refractory to traditional treatments.

Looking ahead, the clinical translation of PRAME modulators faces several challenges, including antigen heterogeneity, immune escape mechanisms, scalability of cell manufacturing, and optimization of dosing strategies. However, the field is rapidly evolving with continuous refinements through combination therapies, innovations in engineering (such as the co-expression of CD8 co-receptors), and the development of advanced bispecific formats with extended half-lives. Such future developments, along with regulatory advancements and strategic trial designs, are expected to bolster the clinical utility of PRAME modulation in oncology.

Ultimately, these efforts are aimed at not only improving clinical outcomes for patients with advanced cancers but also at paving the way for the integration of PRAME modulators as a mainstream therapeutic option. The success of these clinical trials could profoundly impact cancer care by providing new strategies to overcome resistance to conventional therapies and by offering durable responses even in heavily pretreated patient populations. Continued collaboration between academic researchers, biotechnology companies like Immatics, and regulatory agencies will be crucial in refining these therapies and ensuring their successful adoption into clinical practice.

In conclusion, current clinical trials are exploring and advancing multiple PRAME modulators with distinct modalities—from adoptive TCR-T cell therapies to innovative bispecific TCR-based agents—each promising significant therapeutic benefits. The overall approach combines broad immunological engagement with precise targeting of tumor-associated antigens, and this dual-function strategy could potentially revolutionize the treatment landscape for various solid tumors. The encouraging early efficacy and safety data, coupled with plans for adaptive, multi-cohort, and registrational trial designs, suggest a bright future for PRAME modulation as a key pillar in next-generation cancer immunotherapy.