Complete response of RCC to autologous T cell immunotherapy following progression on immune checkpoint inhibitor, A case report

doi:10.21203/rs.3.rs-1750504/v1

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Case Report

Complete response of RCC to autologous T cell immunotherapy following progression on immune checkpoint inhibitor, A case report

https://doi.org/10.21203/rs.3.rs-1750504/v1

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Background: The renal clear cell carcinoma (RCCC) is a frequent occurrence of kidney cancer, such tumor was concealed progressed until symptomatic developed or through imaging examination. More recently, targeted therapies, immunotherapy and their combinations have improved outcome .However seeking the novel salvage treatment of second-line or above of post-immunotherapy has been warranted.

Case presentation: A 55-year-old man diagnosed with non-VHL associated renal clear cell carcinoma presented 8 years ago. The upper abdominal distention and hematochezia were noticed after 6 years of nephrectomy, surgically confirmed pancreas-duodenal metastatic lesions 1.5 years ago to preclude the second primary carcinoma. Despite eight cycles of pembrolizumab plus axitinib after surgery, liver multiple masses progress rapidly. Following four cycles of autologous adoptive T cell immunotherapy and hyperthermia with low dose pembrolizumab, all metastatic lesions demonstrated complete responses. No serious adverse events were reported.

Conclusions: This triple combination of adoptive T cell therapy, low dose immune checkpoint blockade, and hyperthermia has been salvage treatment for RCCC.

The renal clear cell carcinoma

Immune checkpoint inhibitor

Autologous T cell immunotherapy

Hyperthermia

The renal clear cell carcinoma (RCCC) is a frequent occurrence of kidney cancer, such patient was concealed progressed until symptomatic developed or through imaging examination. Metastatic clear cell renal cell carcinoma (ccRCC) has historically demonstrated poor outcome with median survival of 13 months and 5-year survival < 10% [1–2]. RCCC was a consensus recognized tumor responsive to the immunotherapy. The IL-2 cytokine therapy was recommended in the early 1991 as the classic treatment followed by high dose IL-2 and interferon alpha.[3]

More recently, targeted therapies, immunotherapy and their combinations have improved outcome [4], but the efficacy of second-line immunotherapy following failure of first line immune checkpoint blockade is less clear. We present the case of a patient who progressed on the situations of medications of IL-2 ,interferon -gamma ,immune checkpoint blockade and molecular target therapy but experienced a complete response to adoptive T cell immunotherapy combined with hyperthermia.

The patient initially underwent nephrectomy for clinical stage T1N0M0 ccRCC. Interleukin-2 and thymosin were administered. Six years after nephrectomy, he presented with abdominal distention and hematochezia. CT scans demonstrated a mass of 5.5cm ⋅ 5.0cm⋅5.0 cm between the pancreas and duodenum (Fig. 1-A). Pancreaticoduodenectomy was performed and pathology was consistent with metastatic ccRCC [IHC staining revealed CAIX(+), CD10(+), CD117(-), CK(+), CK7(-), P504S(+), PAX-2(+), PAX-8(+), RCC(+), TFE-3(-),Vimentin (partial +)]. One month following surgery, PET /CT showed multiple nodules with high metabolic radio imagines were scanned at S5 segment of the liver, multiple low-density nodules with metabolic free were also detected, FDG avid hepatic metastases (Fig. 1-B). The combination of pembrolizumab plus axitinib was initiated for consecutive eight cycles; however, an MRI reported progressively enlarging masses in the liver and the patient experienced decreased performance status, weight loss, pain of the limbs and nausea (Fig. 1-C).

Although the patient received the standard treatment by both immune check point inhibitor and advanced tyrosine kinase inhibitors for 8 cycles, the side effects were prevalent along the dose accumulation, preferably caused by axitinib, the physical exam was shown the progressive disease with apparent body weight loss and intolerable ECOG performance score decreased. Hepatomegaly was also palpable with general pain. The physicians have discussed through the multiple discipline team to consider the subsequential recommendations for salvage treatment. Withdrawal of both inhibitors for enrollment of tripartite therapy, which calendared autologous adoptive T cell immunotherapy, biweekly hyperthermia of Thermotron RF-8 and low dose of pembrolizumab (100 mg, for every three weeks). The herein autologous adoptive T cell immunotherapy was termed as the retronectin-activated killer cells (RAK). 50 ml peripheral blood was collected to isolate the lymphocytes. The lymphocytes were induced by IL-2 and retronectin to induce the CD8 + T cell immunotherapeutic products. As our previously prepared in the last two decades. One therapeutic schema of tripartite included two cycles of 42.6 billion of RAKs (each cycle formed 3 cellular infusions), one cycle of hyperthermia (twice per week, total 10 times) and 100 mg pembrolizumab per 3 weeks.

1. The quality of life

Two months after surgery, PET/CT in December 2020 suggested liver metastasis. Eight cycles of PD-1 immunotherapy combined with axitinib targeted therapy were then given. In late April 2021, examination showed that the number and size of tumor metastasis increased, and the patient's body weight decreased by 22 lb and physical strength decreased significantly.

The first course of hyperthermia was started on May 4, 2021, during which 2 courses of cell therapy were performed. The patient gained 6.6 lb and returned to normal mentally and physically. The second course of hyperthermia began on June 20, 2021. During the hyperthermia, cell therapy was performed for 3 times. The mental and physical condition remained normal, and the body weight gained 4.4 lb again. In September 2021, the patient received the third course of hyperthermia. During the hyperthermia, he received cell therapy once. His mental and physical condition remained normal, and body weight gained 11 lb again. Up to now, the patient's body weight has increased to about 154 lb. (The curve of body weight was shown in Fig. 2)

2. Imaging

PET/CT followed up at the 2 cycles of tripartite therapy, at least partial remission of liver metastases was confirmed, disappearance of hepatomegaly. The patient continued to receive two more cycles of tripartite, complete response (CR) was achieved, and has persisted more than five months (Fig. 3). No immune mediated adverse events have been observed.

In the case presented, standard immune checkpoint blockade plus vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI) therapy was administered for metastatic disease. At the time of progression, autologous adoptive CD8 + T cells, generated in vitro with IL-2 and RAK cells, were administered with low dose pembrolizumab resulting in a complete response. We believe that the RAKs are primarily responsible for the efficacy. Prior to the development of targeted therapies and immune checkpoint blockade, ccRCC was treated in some patients with high dose IL-2 [3]; however, side effects were substantial and the CR rate was only 4–6%. This patient had already received pembrolizumab and the low dose of pembrolizumab used with the RAK is therefore unlikely to have been the major reason for the complete response. Others and we have previously demonstrated that autologous cytokine induced killer cells, alone or combined with other anti-cancer therapies, could control tumor progression [5–9]. These cytokine-induced killer cells likely provide a source of activated T cells that can overcome exhausted T cells in the tumor microenvironment [7,9,10]. We also incorporated hyperthermia with the goal of activating immune signaling pathways. Previously, we performed a prospective phase I study that demonstrated the safety for hyperthermia in combination with adoptive T cell therapy and encouraging clinical responses in patients with advanced pre-treated solid tumors [11]. Hyperthermia could play a significant role in immunomodulation through at least two ways. First, hyperthermia can enhance the expression of heat shock proteins (HSPs), involved in various processes of immunogenic cell death and as antigen chaperones to antigen-presenting cells (APCs) [12,13]. Moreover, hyperthermia may increase tumor antigen spreading to facilitate antigen cross-presentation by dendritic cells (DCs), resulting in activation of tumor-specific cytotoxic T cells[14,15].

This research has some limitations. Although it was complied with the immunotherapy approach since the initial and more lines treatments, we have explored the implantation of adoptive T cell immunotherapy combined with hyperthermia to achieve the complete remission. The overall survival duration has surpassed 8 months without relapse or metastasis, this model has been applied to other solid tumors with the similar clinical responses. The case is single RCCC represented and need more cases to obtain more data.

This triple combination of adoptive T cell therapy, low dose immune checkpoint blockade, and hyperthermia has been effective in advanced RCCC. The different anti-cancer mechanisms were orchestrated with well-tolerated.

RCCC: The renal clear cell carcinoma

VHL: Von Hippel-Lindau

ccRCC: clear cell renal cell carcinoma

IL-2: Interleukin-2

PET/CT: Positron Emission Computed Tomograph

FDG: F-18-Deoxyglucose or Fluorodeoxyglucose

ECOG: Eastern Cooperative Oncology Group

RAK: Retronectin-activated killer cells

CR: Complete response

VEGFR: Vascular endothelial growth factor receptor

TKI: tyrosine kinase inhibitor

APCs: Antigen-presenting cells

DCs: Dendritic cells

Ethics approval and consent to participate

The clinical study was approved by the Ethics Committee of Fudan University Pudong Medical Center(2021-IIT-021-E02); Written informed consent was obtained from the patient’s next kin for publication of this case report and any accompanying images.

Consent for publication

All case reports were published with the consent of publication.

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no competing interests.

Funding

This work was funded in part by the Construction plan of Clinical Plateau subject of Pudong New Area Health Commission, PWYgy2021-01.

Authors’ contributions

JR: as the chief physician for developing such an innovational approach , reviewed the literature and composed the manuscript. TCW, CCL,XLW,LNH,CXZ and KW : treated the patient and collected the data. XNZ, XHB: clinical research manager for legal documentation and data inquiry for ensuring quality of data collections and analysis. JJL, XDL: PET/CT image analysis to evaluation of clinical response. . BS: Adoptive T cell culture. AH: clincal research protocol check and accuracy endorsement. MAM: clinical data and treatment plan check and manuscript modification of language. HKL: study design discussion and future plan. All authors read and approved the final manuscript.

Acknowledgements

Not applicable

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No competing interests reported.

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Complete response of RCC to autologous T cell immunotherapy following progression on immune checkpoint inhibitor, A case report

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