Neo-Adjuvant Chemo/Immunotherapy in the Treatment of Stage III (N2) Non-Small Cell Lung Cancer: A Phase I/II Pilot Study

Abstract

In a previous randomized study, we showed that adjuvant immunotherapy with tumor-infiltrating lymphocytes and recombinant interleukin-2 (rIL-2) significantly improved survival in resected N2-Non Small Cell Lung Cancer (NSCLC) patients. The present study assesses feasibility, safety and potential efficacy of combined neo-adjuvant chemotherapy and immunotherapy with peripheral blood mononuclear cells (PBMC) and rIL-2 in resectable N2-NSCLC patients. Eighty-two consecutive N2-NSCLC patients underwent neo-adjuvant chemotherapy with cisplatin and gemcitabine. Out of the 82 patients, 23 were also subjected to leukapheresis prior to neo-adjuvant chemotherapy while the remaining 59 did not. Collected PBMC were analyzed for viability and phenotype and then stored frozen in liquid nitrogen. Thawed PBMC were infused intravenously, 5 days before surgery. After the infusion, rIL-2 was administered subcutaneously until surgery. Only patients with a partial or complete response to neoadjuvant chemotherapy underwent surgery: 13 patients in the experimental immunotherapy group (A) and 32 in the reference group (B). The two groups were homogeneous for all major prognostic factors. Median leukapheresis yield was 10 billion PBMC, (range 3–24 billions). Two to six billion PBMC were infused. The phenotypic analysis showed that similar proportions of CD4 and CD8 cells were present in leukapheresis products, and thawed PBMC, as well as in T lymphocytes isolated from the removed tumours. No severe adverse effects were observed following immunotherapy. No significant differences in overall survival (OS) and event-free survival (EFS) were seen between the two groups. However, the 5-year OS in group A was almost twice as much compared to group B (59% vs 32%). After adjustment for major prognostic factors, a statistically significant 66% reduction in the hazard of death was seen in patients receiving immunotherapy. The OS benefit was more evident in patients with adenocarcinoma than in those with squamous cell carcinoma. This study supports the favorable toxicity profile and potential efficacy of combining neo-adjuvant chemotherapy and immunotherapy with PBMC and rIL-2 in the treatment of N2-NSCLC patients.

Keywords

non-small cell lung cancer neo-adjuvant immunotherapy neo-adjuvant chemotherapy surgery survival

References

Ratto

Zino

Mirabelli

. A randomized trial of adoptive immunotherapy with tumor-infiltrating lymphocytes and interleukin-2 versus standard therapy in the postoperative treatment of resected non-small cell lung carcinoma. Cancer 1996;78:244–51.

Ratto

Cafferata

Scolaro

Bruzzi

Alloisio

Costa

Spessa

Semino

Melioli

. Phase II study of combined immunotherapy, chemotherapy, and radiotherapy in the postoperative treatment of advanced non-small-cell lung cancer. J Immunother 2000; 23:161–67.

Lissoni

Barni

Ardizzoia

Olivini

Brivio

Tisi

Tancini

Characiejus

Kothari

. Cancer immunotherapy with low-dose interleukin-2 subcutaneous administration: Potential efficacy in most solid tumor histotypes by a concomitant treatment with the pineal hormone melatonin. J Biol Regul Homeost Agents. 1993; 7:121–25.

Kimura

. Post-surgical adjuvant chemo-immunotherapy by activated autologous killer cells and dendritic cells from regional lymph nodes of the lung cancer patients. Lung Cancer 2005; 49: S79.

Butts

Murray

Maksymiuk

. Randomized phase IIB trial of BLP25 liposome vaccine in stage IIIB and IV non-small-cell lung cancer. J Clin Oncol. 2005;23:6674–81.

Butts

Maksymiuk

Goss

. A multi-centre phase IIB randomized controlled study of BLP25 liposome vaccine (L-BLP25 or Stimuvax) for active specific immunotherapy of non-small cell lung cancer (NSCLC): Updated survival analysis: B1-01. J Thorac Oncol 2007; 2:S332–33.

Vansteenkiste

Zielinksi

Linder

. Activity of MAGE-A3 cancer immunotherapeutic as adjuvant therapy in stage IB/II non-small cell lung cancer (NSCLC): Final results of a multi-center, double-blind, randomized, placebo-controlled phase II study: B1-05. J Thorac Oncol 2007; 2:S334–35.

Skitzki

Craig

Okuyama

Knibbs

McDonagh

Chang

Stoolman

. Donor cell cycling, trafficking, and accumulation during adoptive immunotherapy for murine lung metastases. Cancer Res 2004; 64:2183–91.

Shields

. The significance of ipsilateral mediastinal lymph node metastasis (N2 disease) in non-small cell carcinoma of the lung. J Thorac Cardiovasc Surg 1990; 99:48–53

10.

Watanabe

Shimizu

Oda

Hayashi

Watanabe

Tatsuzawa

Iwa

Suzuki

Takashima

. Aggressive surgical intervention in N2 non-small cell cancer of the lung. Ann Thorac Surg 1991; 51:253–61

11.

Melioli

Ratto

Guastella

. Isolation and in vitro expansion of lymphocytes infiltrating non-small cell lung carcinoma: Functional and molecular characterisation for their use in adoptive immunotherapy. Eur J Cancer 1994; 30:97–102.

12.

Del Mastro

Venturini

Viscoli

. Intensified chemotherapy supported by DMSO-free peripheral blood progenitor cells in breast cancer patients. Ann Oncol 2001; 12:505–8.

13.

Robinson

Wagner

Jr Ruckdeschel

; American College of Chest Physicians. Treatment of stage IIIA non-small cell lung cancer. Chest 2003; 123:202–20S.

14.

Robinson

Ruckdeschel

Wagner

Jr Stevens

. American College of Chest Physicians. Treatment of non-small cell lung cancer-stage IIIA. ACCP evidence-based clinical practice guidelines (2nd edition). Chest 2007; 132:243–265S.

15.

Hirschowitz

Yannelli

. Immunotherapy for lung cancer. Proc Am Thorac Soc 2009; 6:224–32.

16.

Lissoni

Fumagalli

Brivio

Rovelli

Messina

Di Fede

Colciago

Brera

. Cancer chemotherapy-induced lymphocytosis: A revolutionary discovery in the medical oncology. J Biol Regul Homeost Agents 2006; 20:29–35.

17.

Imai

Sunaga

Shimizu

. Clinicopathological and therapeutic significance of CXCL12 expression in lung cancer. Int J Immunopathol Pharmacol 2010; 23:153–64