MITI: A Breakthrough Approach in Treating Metastatic Cancer with Localized Immunotherapy

Can MITI Revolutionize Treatment for Metastatic Cancer?

The treatment of metastatic cancer presents an ongoing challenge, with conventional first- and second-line therapies, including chemotherapy and immunotherapy, rarely offering curative outcomes. A recent phase II clinical trial presents a novel approach to addressing this challenge through Multiplex IntraTumoral Immunotherapy (MITI), a localized treatment strategy that combines multiple immunostimulatory mechanisms to generate personalized antitumor immunity. The trial, registered as NCT04713371, investigated the safety and efficacy of MITI with RP-01-5001 in patients with metastatic solid cancers who had failed standard therapies. This innovative approach represents a significant departure from conventional systemic immunotherapy methods, potentially offering new hope for patients with limited treatment options while minimizing systemic toxicity that typically accompanies immunotherapy regimens.

What Innovative Mechanisms Drive MITI?

MITI with RP-01-5001 incorporates five distinct and complementary immunostimulatory mechanisms to optimize antitumor effects. The first mechanism involves controlled cellular lysis through cryoablation, which releases the full spectrum of patient-specific cancer antigens while preserving their structural integrity for maximum antigenicity. This process carefully controls necrosis and necroptosis, limiting cell destruction to a small focus (≤1.0 cm diameter) within each treated cancer site while preserving the surrounding blood and lymphatic vasculature. This preservation is crucial as it allows immune cells to enter and exit the site while maintaining intimate contact with both damaged and undamaged cancer cells, damage-associated molecular patterns (DAMPs), cytokines, and other immunostimulants. The second mechanism involves "unmasking" cancer antigens through PD-1 inhibition with pembrolizumab, which exposes these antigens to dendritic cells and cytotoxic T-cells while facilitating T-cell antitumor activity and reversing T-cell exhaustion. The third mechanism employs CTLA-4 blockade with ipilimumab and low-dose cyclophosphamide to suppress inhibitory signals from regulatory T-cells, potentiating and prolonging the cytotoxic T-cell response. Additionally, collagen hydrogel is injected to minimize drug leakage. The fourth mechanism utilizes daily subcutaneous sargromostim (GM-CSF) to mobilize immune cells from bone marrow, suppress T-regulatory cell inhibitory signals, and promote humoral and cell-mediated responses. The final mechanism harnesses the abscopal effect, whereby the localized treatment triggers a systemic immune response capable of targeting distant metastases.

Who Participated in This Pioneering Trial?

The single-institution trial enrolled thirteen patients, including twelve with metastatic solid cancers and one with sacral chordoma. The patient population consisted of adults with at least one imaging or histologically-proven metastasis measuring at least 1.0 cm in diameter, all of whom had failed conventional therapies. The cohort included diverse cancer types: prostate (four patients), sarcoma (two patients), and one each of breast, colon, bladder, uterine cervix, tongue, kidney, and sacral chordoma. The mean age was 67.2 years (range 38-87 years), with four female participants (30.8%). The treatment protocol involved administration of low-dose oral cyclophosphamide for 3-5 days before MITI, followed by CT-guided cryoablation using a 1.7 mm diameter short freeze-segment probe to create approximately 2.0 cm diameter iceballs. After a brief thawing period, the ablated sites were injected with the RP-01-5001 combination: 50 mg of pembrolizumab, 10 mg of ipilimumab, and 20 mg of cyclophosphamide, followed by collagen hydrogel to prevent back-oozing. Patients also received daily subcutaneous sargromostim (GM-CSF) for four weeks. Each patient could receive up to three treatment cycles at four-week intervals, with eight patients completing all three cycles, two receiving two cycles, and three receiving only one cycle.

What Promising Efficacy Findings Have Emerged?

The trial demonstrated promising efficacy outcomes, with a disease control rate of 77%, including complete response in 7.7% of patients, partial response in 30.8%, and stable disease in 38.5%. The best response ranged from 0 to 91%, with a mean of 38% for responding patients. Notably, an injection site response was observed in nine patients (69%), while a distal abscopal effect was seen in four patients (31%), including complete resolution of lung metastases in a sarcoma patient and resolution of lung and liver metastases in a bladder cancer patient. The median progression-free survival was 5.4 months (95% CI: 1.8 to 23.1 months), and the median overall survival was 20.9 months (95% CI: 9.1 to 22.8 months). These results are particularly significant given that all patients had failed conventional therapies and many were eligible for hospice care at study entry. One particularly noteworthy case involved an adult patient with grade 4 myxoid fibrosarcoma who had undergone left arm amputation and radiotherapy but was intolerant to chemotherapy. After developing widespread metastases, the patient received two cycles of MITI, resulting in the resolution of all but rib metastases within two months, with only transient injection site discomfort as an adverse event.

Does MITI Offer a Superior Safety Profile?

Safety data from the trial revealed a favorable toxicity profile compared to systemic immunotherapy approaches. The adverse event rate was 69%, with most events being grade 1 or 2. Only two transient grade 3 events (15%) were reported: a pneumothorax and pneumonia immediately following MITI, neither requiring hospitalization. The most common adverse events were skin rash and transient diarrhea, invariably attributed to sargromostim administration. This safety profile compares favorably to historical data for systemic second-line or salvage immunotherapy, which typically shows higher rates of grade 3 treatment-related adverse events. For example, in patients with metastatic bladder cancer receiving second-line systemic PD-1/L1 therapy, grade 3 treatment-related adverse events occur in approximately 17% of cases, with immune-related adverse events in 8%. The favorable toxicity profile of MITI suggests that the intratumoral route of administration may indeed reduce systemic exposure while maintaining therapeutic efficacy, potentially offering a better quality of life for patients requiring salvage therapy.

Could Imaging Misread True Responses?

An interesting finding from the study was the discrepancy between post-treatment imaging and histopathology. Seven patients underwent biopsy of CT-positive presumptive residual cancer at sites of prior MITI treatment, but only three were positive for malignancy. The other four (57%) had shrunken residual masses of fibrous tissue, termed "pseudoresiduum," all associated with partial or complete clinical response. This phenomenon required modification of the iRECIST criteria used in the study, with preference given to histopathology over imaging when available. The high rate of pseudoresiduum highlights a critical consideration for future intratumoral immunotherapy trials: radiographic imaging may significantly underestimate objective responses, potentially leading to unnecessary additional treatments. This finding suggests that biopsy confirmation should be considered when evaluating response to intratumoral immunotherapy, particularly when making decisions about subsequent treatment strategies. The pseudoresiduum phenomenon differs from pseudoprogression, which refers to an apparent increase in tumor size due to inflammatory infiltrates rather than true disease progression.

What Study Limitations Should We Consider?

Despite the promising results, the study has several limitations that warrant consideration. The small and heterogeneous patient cohort, along with the absence of a control arm, restricts the robustness of efficacy assessments. The relatively high rate of treatment discontinuation (38%) raises questions about tolerability and patient selection, though it's worth noting that many participants traveled from out of state for treatment, potentially affecting retention. Additionally, some patients received subsequent conventional therapies following progression, potentially confounding overall survival outcomes. The intratumoral drug doses were empirically determined from phase 1 experience and extrapolated from intravenous and parenteral administration data, suggesting that optimal dosing for intratumoral delivery may not yet be established. The small sample sizes of individual cancer subgroups precluded meaningful statistical subgroup analyses, emphasizing the need for larger, more focused studies to establish efficacy in specific cancer types.

Might MITI Reshape Future Metastatic Cancer Therapy?

This first-in-human prospective clinical trial of MITI represents a significant step forward in developing novel immunotherapeutic approaches for patients with metastatic cancer who have exhausted standard treatment options. By combining controlled cryoablation with localized administration of immune checkpoint inhibitors and immune modulators, MITI appears to effectively stimulate personalized antitumor immunity while avoiding many of the toxicities associated with systemic immunotherapy. The observed abscopal responses suggest that this localized approach can indeed generate systemic antitumor effects, potentially addressing one of the key challenges in treating metastatic disease. Could this localized, multipronged approach to immunotherapy represent a paradigm shift in how we approach salvage therapy for metastatic cancer patients? As researchers continue to refine this approach, might we see increased emphasis on histopathologic validation alongside conventional imaging criteria when evaluating immunotherapy responses? The promising results of this small trial certainly warrant larger, controlled studies to definitively establish the therapeutic potential of MITI as a novel treatment approach for patients with limited options.

Summary

A phase II clinical trial investigated Multiplex IntraTumoral Immunotherapy (MITI) with RP-01-5001 in thirteen patients with metastatic solid cancers. The treatment combines five immunostimulatory mechanisms: controlled cellular lysis through cryoablation, PD-1 inhibition, CTLA-4 blockade, GM-CSF administration, and the abscopal effect. The trial showed a 77% disease control rate, with complete response in 7.7%, partial response in 30.8%, and stable disease in 38.5% of patients. The median progression-free survival was 5.4 months, and overall survival was 20.9 months. MITI demonstrated a favorable safety profile with mostly grade 1-2 adverse events. The study revealed an important finding regarding "pseudoresiduum," where imaging may underestimate treatment response, suggesting the need for histopathological confirmation in future trials.