An open-label single-center investigator-initiated exploratory clinical study in patients with refractory or recurrent solid tumors: ‘R-ISV-FOLactis’ trial

doi:10.21203/rs.3.rs-3140587/v1

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An open-label single-center investigator-initiated exploratory clinical study in patients with refractory or recurrent solid tumors: ‘R-ISV-FOLactis’ trial

https://doi.org/10.21203/rs.3.rs-3140587/v1

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Background: As a breakthrough tool for cancer immunotherapy, the therapeutic cancer vaccine, which includes personalized neoantigen vaccine and in situ vaccine, is in rapid development. In situ vaccination can be realized by radiotherapy and intratumoral immune injection. Additionally, immune checkpoint inhibitor is a common treatment modality for tumors. This study proposes to combine intratumoral injection, radiotherapy, and PD-1 inhibitors for patients with recurrent or metastatic solid tumors and subsequently evaluate the efficacyand safety.

Methods/design: This exploratory clinical study is designed as an open-label, single-center trial aimed at treating patients with advanced solid tumors who are unresponsive or intolerable to standard treatment. Patients will be treated with hypofractionated radiotherapy, intratumoral injection of FOLactis, and PD-1 blockades. Additionally, 300mg cyclophosphamide will be added during intravenous administration of PD-1 blockades to inhibit regulatory T cells. Immune maintenance therapy with PD-1 blockades will be administered every three weeks until disease progression or the emergence of intolerable toxicity. The primary endpoint of this study is to observe the objective efficacy and safety of the combined regimen, with the secondary endpoint to evaluate abscopal effects and the correlation between the immunological rationale and efficacy.

Discussion: Both radiotherapy and intratumoral immune injection are approaches to conducting in situ vaccination. Their combination can enhance anti-tumor immunity by targeting multiple links of the cancer-immunity cycle. PD-1 blockade, a kind of immune checkpoint inhibitor, has garnered significant attention in tumor immunotherapy research in recent years. In this study, a triple combination of radiotherapy, intratumoral immune injection, and intravenous PD-1 inhibitor will be utilized to treat patients with advanced solid tumors to trigger antitumor immunity. The combined treatment is expected to be feasible and effective and provide a novel option for the comprehensive treatment of cancer.

Trial registration: ChiCTR. gov.cn: ChiCTR2200060660.

in situ vaccination

radiotherapy

intratumoral injection

immune checkpoint inhibitors

probiotics

Since immune checkpoint inhibitors (ICIs) were approved for application by the Food and Drug Administration (FDA) in 2014, clinical studies of monoclonal antibodies targeting programmed cell death protein-1 (PD-1) inhibitors have taken off in leaps and bounds. However, there are many patients unresponsive, hyperprogressive, or resistant^[1]. There are many questions to be addressed, such as predictive biomarkers, mechanisms of resistance, and immune-related adverse events (irAEs) ^[2–4]. Therefore, PD-1 inhibitors sometimes need to be combined with other immunosensitizing tools such as radiotherapy or chemotherapy to enhance the anti-tumor immunity and improve the objective response rate of patients^[5].

Radiotherapy is one of the most important modalities of tumor treatment, which can damage the DNA of tumors and induce immunogenic cell death (ICD), thus releasing a large amount of tumor-reactive antigens for immune cells to recognize^[6]. It is expected to promote tumor reduction or even regression by producing lethal damage to tumor cells, mainly by causing double-strand breaks (DSB) in DNA^[6], while controlling the surrounding normal cells to be irradiated at a low dose. Approximately 50% of patients suffering from tumors will receive radiotherapy as part of their treatment. In addition to local control of the tumor irradiated, shrinkage of the lesion outside the field of irradiation is occasionally observed. The phenomenon is known as the ‘abscopal effect’^[7], which confirms that radiotherapy is not only a local treatment for tumors but also can stimulate systemic anti-tumor immunity. By promoting the maturation of dendritic cells (DCs) and antigen presentation, it can reverse the immunosuppressive tumor microenvironment (TME) to a certain extent^[8]. This shows that radiotherapy is one of the ways to conduct in situ vaccination^{[9, 10]}. In situ vaccination is a method to reverse suppressive TME, stimulate tumor immunogenicity and promote the body to produce tumor-specific T cells by radiotherapy or intratumoral injection^{[11, 12]}. The efficacy of radiotherapy alone is often unsatisfactory. So we want to construct a “composite in situ vaccination” by combining radiotherapy with intratumoral immune injection to boost antitumor immunity.

Intratumoral immune injection^[13] refers to the local injection of immuno-modulatory drugs such as immune cells, ICIs, oncolytic viruses, cytokines, toll-like receptor (TLR) agonists, bacteria, and toxins into the tumor to promote the release of large number of antigens, thus forming an "antigen factory", enhancing the capacity of antigen-presenting cells (APCs) and increasing the killing effect of T lymphocytes on tumor cells to enhance anti-tumor immunity. We have developed a bifunctional engineered Lactococcus lactis (FOLactis) delivering an encoded fusion protein of fms-like tyrosine kinase 3 ligand (Flt3L) and OX40 ligand (OX40L)^[14]. Intratumoral injection of FOLactis destructs tumor cells by cell lysis and a robust anti-bacteria response can be induced, meanwhile releasing large amounts of tumor-associated antigens (TAA) or tumor-specific antigens (TSA), which bind to bacterial-associated danger signals such as lipopolysaccharide(LPS) or other pathogen-associated molecular patterns (PAMPs), then promote antigen cross-presentation of DCs in TME and tumor-draining lymph nodes (TDLNs), especially CD103⁺CD11c⁺ and CD8α⁺CD11c⁺ DCs. Preclinical study showed that FOLactis significantly enhanced anti-tumor immunity and successfully converted “cold” tumors into “hot” ones.

In this study, we propose to combine intratumoral injection of FOLactis, radiotherapy with ICIs to induce a systemic anti-tumor immune response and improve the therapeutic effect in patients with refractory or recurrent solid tumors.

Recruitment and allocation

The eligibility criteria are as follows:

Patients aged 18-80 years old.
Eastern Cooperative Oncology Group (ECOG) performance status of score 0-2.
Disease progression occurs despite standard treatment for pathologically confirmed recurrent or metastatic solid tumors, or rejection/intolerance of standard treatment.
Patients with one or more measurable lesions according to the Response Evaluation Criteria in Solid Tumours (RECIST1. 1), at least one lesion suitable for ≥5Gy/Fx radiotherapy and intratumoral injection.
Life expectancy ≥ 12 weeks.
Adequate bone marrow, hepatic, cardiac and renal functions.
Patients need to be eluted for at least 1 cycle for radiotherapy or for 5 half-lives for drugs.
Women of childbearing age with a negative pregnancy test (serum or urine) within 14 days prior to enrollment should voluntarily uptake an appropriate method of contraception during the observation period and within 3 months after the last drug administration of the trial. For men, they should be surgically sterilized or consent to an appropriate method of contraception during the observation period and within 3 months after the last drug administration of the trial.
The toxicity from prior treatment has recovered to ≤1 level.
Patients who can provide informed consent.

The exclusion criteria are as follows:

Patients have undergone major surgery within 4 weeks prior to enrollment.
Unsatisfactory control of hypertension (sustained elevation of systolic blood pressure ≥150 mmHg or diastolic blood pressure≥100 mmHg) even after drug treatment;

Patients with uncontrolled clinical cardiac symptoms or disease, including:

Heart failure with NYHA class II and above;
Unstable angina pectoris;
Myocardial infarction occurred within 1 year;
Patients with clinically significant supraventricular or ventricular arrhythmias requiring clinical intervention.

Any active autoimmune disease or history of autoimmune disease (e.g. interstitial pneumonia, uveitis, enterocolitis, hepatitis).

Patients with congenital or acquired immune deficiency.

Patients with serious infection within 4 weeks or unexplained fever >38.5℃;

Patients with arterial/venous thrombotic events such as cerebrovascular accidents, deep vein thrombosis and pulmonary embolism that occurred within the 6 months prior to enrollment;

Patients who are known to be allergic to any drug involved in the trial;

Patients with history of definite neurological or psychiatric disorders, including epilepsy and dementia;

Patients with known uncontrolled or symptomatic active central nervous system metastasis characterized by clinical symptoms, cerebral edema, spinal cord compression, carcinomatous meningitis, soft meningeal disease, and/or progressive growth;

Other conditions deemed unsuitable for inclusion by the researchers.

Trial design

This is an open-label, single-center, exploratory clinical trial conducted in Drum Tower Hospital, beginning from April 2022, in which patients with refractory or recurrent solid tumors after standard therapy will receive radiotherapy, intratumoral injection of FOLactis, and intravenous PD-1 monoclonal antibody (Fig.1). Firstly, patients will receive radiotherapy from day 1 to day 3 and on day 22, with a planned dose of 8Gy. Secondly, a novel engineered Lactococcus lactis (FOLactis), which expresses Flt3L-OX40L fusion protein, will be injected into the tumor locally on day 3, day 6, day 22, and day 28. Finally, PD-1 inhibitors will be used intravenously on day 1, which needs to be administered within 48 hours of the radiotherapy’s end, and immune maintenance therapy will be administered every 21 days. Moreover, PD-1 blockade needs to be combined with 300mg cyclophosphamide, which inhibits Tregs to further stimulate anti-tumor immunity.

The primary endpoint of this study is the objective response rate (ORR). The secondary study endpoints include disease control rate (DCR), progression-free survival time (PFS), time-to-progression (TTP), overall survival (OS), clinical benefit rate (CBR) and adverse events (AEs). The exploratory endpoints include the abscopal effect and the correlation between immunological parameters and efficacy.

Radiotherapy directly damages DNA and induces ICD, releasing large amounts of TAA or TSA for recognition by APCs. ICD, as a mode of death accompanied by the release of tumor-reactive antigen and damage-associated molecular patterns (DAMPs), is the initiating step of in situ vaccination, providing antigens and adjuvants for the establishment of in situ vaccination^[15]. DAMPs released include adenosine triphosphate (ATP), calreticulin (CRT), high mobility group box 1 (HMGB1) and heat shock proteins (HSPs), which bind to pattern recognition receptors (PRRs) on DCs to promote the maturation and activation of DCs, thus ensuring efficient antigen presentation and T cell initiation^[16–18]. Additionally, several preclinical studies have shown that radiotherapy can promote the normalization of aberrant vasculature, thereby increasing the infiltration of T cells^{[19, 20]}. The expression of natural-killer group 2, member D (NKG2D)-ligands, major histocompatibility complex (MHC) class I, Fas, pro-inflammatory cytokines such as IL-6 or IL-10, chemokines such as CXCL-10 or CXCL-16 can also be upregulated by irradiation^{[15, 18, 21–27]}. The development of radiotherapy technology has given birth to a series of new technologies such as cyberknife, TOMO, and proton radiotherapy, which allow radiotherapy to be more precisely used as an in situ vaccination^[28–30]. However, radiotherapy alone does not induce a robust in situ vaccine effect in most cases and needs to be combined with other therapies to augment the anti-tumor effect. Furthermore, studies have shown that radiotherapy can cause upregulation of programmed death-ligand 1 (PD-L1) expression by acting on signaling pathways such as IFN-γ/STAT3 and thereby weakening radiotherapy-induced antitumor immunity^[31]. Nevertheless, this may be applied to overcome resistance to PD-1 inhibitors^[32]. Multiple preclinical studies have observed that combining radiotherapy with PD-1/PD-L1 monoclonal antibody significantly inhibits the growth of the tumor, improves survival, and induces abscopal effects by reducing myeloid-derived suppressor cells (MDSCs) and restoring the effector function of CD8⁺ T cells compared to monotherapy^{[31, 33–37]}. As a result, radiotherapy combined with PD-1/PD-L1 monoclonal antibodies may be a feasible strategy for combination antitumor therapy.

OX40, a member of the tumor necrosis factor receptor superfamily, which is also known as CD134 or TNFRSF4^+[38], is a costimulatory molecule involved in T cells’ proliferation, effector functions, and surviva. OX40-OX40L interaction can increase CD4⁺ and CD8⁺ T cell populations and the production of cytokines like IFN-γ which can upregulate the expression of PD-L1^[39]. When used in combination with PD-1 or CTLA-4 blockade, tumor immune resistance can be further overcome, ultimately producing a robust therapeutic immune response^[40–43]. OX40 agonist in combination with PD-1 monoclonal antibody showed an increase in effector CD4⁺ and CD8⁺ T cells and a decrease in the number of Treg cells and MDSCs because of the formation of a local immunostimulatory microenvironment^[40]. Similarly, several preclinical studies have been conducted on the combination of OX40 agonist with radiotherapy, which demonstrated that this combination can effectively inhibit local tumor growth and improve survival rate, with increased activation of CD4⁺ and CD8⁺ T cells, depletion of Treg cells, and decreased expression of FOXP3 in TDLNs^{[44, 45]}. In a mouse model of anti-PD-1 resistant lung tumors, intratumoral injection of OX40 agonist antibody after radiotherapy effectively inhibited local tumor growth, limited lung metastasis, and improved survival^[46]. However, the application of OX40 agonist intravenously in human is limited by its unsatisfactory efficacy and irAEs such as diarrhea, fatigue, pyrexia, pneumonitis^{[47, 48]}. In this study, we try to inject OX40 agonist into the tumor to reduce the risk of irAEs and enable the use of multiple synergistic combinations.

Flt3L is a major growth and differentiation factor for hematopoietic progenitor cells and plays a key role in the development of conventional and plasmacytoid DCs, so the intratumoral injection of Flt3L may indirectly supplement DCs^{[12, 49]}. In 1999, Chakravarty P K et al. combined radiotherapy with Flt3L for the first time to reduce lung metastases in a mouse model of Lewis lung cancer^[50]. In 2019, the results of a clinical trial (NCT01976585) for the treatment of indolent non-Hodgkin's lymphoma by intratumoral injection of Flt3L and Poly-ICLC in combination with low-dose radiotherapy showed that 8 of the 11 patients treated achieved CR or PR, suggesting the potential for clinical application of this treatment modality^[51]. Many clinical studies have been performed in which radiotherapy combined with intratumoral injection of Flt3L induced systemic CD8⁺ T-cell anti-tumor immunity, with some patients observed abscopal effects^{[52, 53]}.

On this basis, we try to combine PD-1 inhibitors, radiation therapy, OX40 agonist and Flt3L. The rapid degration limited the efficacy of free Flt3L or OX40 agonists. In order to prevent the fast metabolism of Flt3L and OX40L, we utilized Lactococcus lactis as carrier to ensure persistant effect. Meanwhile, Lactococcus lactis possesses abundant PAMPs to mobilize the immune system. Also, it modulates the natural killer cells, DCs and macrophages by NF-κB signaling pathway. At the dose of FOLactis 10^9 CFU, significant shrinkage was observed in tumors on both the injected side (treated) and the uninjected side, and mice in the FOLactis 10^9 CFU group had the longest survival. It was shown that FOLactis led to significant tumor regression mainly by promoting the proliferation and differentiation of cDC1 and restoring cytotoxic T lymphocyte (CTL) responses in TME. In vitro experiments confirmed the activation function of FOLactis on DCs and T cells. In vivo animal models verified the immune effect of FOLactis as in situ vaccination, which effectively prolonged the survival period of tumor-bearing mice.

Overall, hypofractionated radiotherapy can convert tumors into individualized in situ vaccination, and intratumoral injection of FOLactis can specifically target tumor areas and colonize tumor necrosis centers, thereby activating DCs and T cells and exerting tumor suppressive effects. The combination of radiotherapy and intratumoral injection enhances tumor-specific immunity and produces abscopal effect. When combined with PD-1 inhibitors, the anti-tumor immunity will be augmented. The mechanism of the trial is shown in the Fig. 2. Consequently, we designed this triple regimen to improve the response rate of patients and stimulate abscopal effect by promoting antigen release, increasing the antigen-presenting capacity of APCs, and upregulating the expression of various pro-inflammatory cytokines and PD-L1, thereby improving the therapeutic effect, with the hope of bringing new ideas to the treatment of advanced recurrent or metastatic solid tumors.

In situ vaccination can be conducted by radiation and intratumoral immune injection through targeting multiple links of the cancer-immunity cycle. Preclinical and clinical studys have demonstrated that the exploration of synergistic application of in situ vaccination and systemic immunotherapy such as ICIs is prospective. In this study, we try to treat patients with refractory or recurrent solid tumors by combining radiotherapy, PD-1 blockade and intratumoral injection of FOLactis, and then further evaluate the safety and efficacy of the comprehensive strategy.

ICIs: immune checkpoint inhibitors; FDA: Food and Drug Administration; PD-1: programmed cell death protein-1; irAEs: immune-related adverse events; ICD: immunogenic cell death; DSB: double-strand breaks; DCs: dendritic cells; TME: tumor microenvironment; TLR: toll-like receptor; APCs: antigen-presenting cells; Flt3L: fms-like tyrosine kinase 3 ligand; OX40L: OX40 ligand; TAA: tumor-associated antigens; TSA: tumor-specific antigens; LPS: lipopolysaccharide; PAMPs: pathogen-associated molecular patterns; TDLNs: tumor-draining lymph nodes; ECOG: Eastern Cooperative Oncology Group; RECIST1. 1: Response Evaluation Criteria in Solid Tumours; ORR: objective response rate; DCR: disease control rate; PFS: progression-free survival time; TTP: time-to-progression; OS: overall survival; CBR: clinical benefit rate;AEs: adverse events; DAMPs: damage-associated molecular patterns; ATP: adenosine triphosphate; CRT: calreticulin; HMGB1: high mobility group box 1; HSPs: heat shock proteins;PRRs: pattern recognition receptors; NKG2D: natural-killer group 2, member D; MHC: major histocompatibility complex; PD-L1: programmed death-ligand 1; MDSCs: myeloid-derived suppressor cells; CTL: cytotoxic T lymphocyte.

Acknowledgements

Not applicable.

Ethical statement

The ethics committee of Drum Tower Hospital, approved the study (approval number 2022-101-01). The trial protocol is conducted in accordance with Good Clinical Practice guidelines. All participants have to sign their informed consent before the trial.

Authors’ contributions

Conception and design: B.L. and R.L.; Recruited patients: X.W., J.S. (1) and Q.L.; Member of study management group: J.D., X.C., J.Z., Y.Z., L.M., H.Q., M.T. and J.S. (2) ; Manuscript drafting and substantive revision: J.D. and R.L.

Consent for publication

Not applicable.

Funding

The study was financially supported by the National Natural Science Foundation of

China (82203178 (R.L.)), and the fundings for Clinical Trials from the Affiliated Drum Tower Hospital, Medical School of Nanjing University (2022-LCYJ-MS-09).

Author details

¹Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China. ²Department of Oncology, Taikang Xianlin Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.

Availability of data and materials

Not applicable.

Competing interests

The authors declare that they have no competing interests.

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An open-label single-center investigator-initiated exploratory clinical study in patients with refractory or recurrent solid tumors: ‘R-ISV-FOLactis’ trial

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