Malignant cells have the capacity to rapidly grow exponentially and spread in part by suppressing, evading, and exploiting the host immune system. Immunotherapy is a form of oncologic treatment directed towards enhancing the host immune system against cancer. In recent years, manipulation of immune checkpoints or pathways has emerged as an important and effective form of immunotherapy. Agents that target cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), programmed cell death receptor-1 (PD-1), and programmed cell death ligand-1 (PD-L1) are the most widely studied and recognized. Immunotherapy, however, extends beyond immune checkpoint therapy by using new molecules such as chimeric monoclonal antibodies and antibody drug conjugates that target malignant cells and promote their destruction. Genetically modified T cells expressing chimeric antigen receptors are able to recognize specific antigens on cancer cells and subsequently activate the immune system. Native or genetically modified viruses with oncolytic activity are of great interest as, besides destroying malignant cells, they can increase anti-tumor activity in response to the release of new antigens and danger signals as a result of infection and tumor cell lysis. Vaccines are also being explored, either in the form of autologous or allogenic tumor peptide antigens, genetically modified dendritic cells that express tumor peptides, or even in the use of RNA, DNA, bacteria, or virus as vectors of specific tumor markers. Most of these agents are yet under development, but they promise to be important options to boost the host immune system to control and eliminate malignancy. In this review, we have provided detailed discussion of different forms of immunotherapy agents other than checkpoint-modifying drugs. The specific focus of this manuscript is to include first-in-human phase I and phase I/II clinical trials intended to allow the identification of those drugs that most likely will continue to develop and possibly join the immunotherapeutic arsenal in a near future.
Zhang X, Yang Y, Fan D, Xiong D. The development of bispecific antibodies and their applications in tumor immune escape. Exp Hematol Oncol. 2017;6:12.
Fan G, Wang Z, Hao M, Li J. Bispecific antibodies and their applications. J Hematol Oncol. 2015;8:130.
Kim RD, Arlen PM, Tsang KY, et al. Ensituximab (E) in patients (pts) with refractory metastatic colorectal cancer (mCRC): results of a phase I/II clinical trial. J Clin Oncol. 2017;35:3081.
Tabernero J, Melero I, Ros W, et al. Phase Ia and Ib studies of the novel carcinoembryonic antigen (CEA) T-cell bispecific (CEA CD3 TCB) antibody as a single agent and in combination with atezolizumab: preliminary efficacy and safety in patients with metastatic colorectal cancer (mCRC). J Clin Oncol. 2017;35:3002. CrossRef
Wu J, Fu J, Zhang M, Liu D. Blinatumomab: a bispecific T cell engager (BiTE) antibody against CD19/CD3 for refractory acute lymphoid leukemia. J Hematol Oncol. 2015;8:104.
Tolcher AW, Alley EW, Chichili G, et al. Phase 1, first-in-human, open label, dose escalation study of MGD009, a humanized B7-H3 x CD3 dual-affinity re-targeting (DART) protein in patients with B7-H3-expressing neoplasms or B7-H3 expressing tumor vasculature. J Clin Oncol. 2016;34:TPS3105. CrossRef
Angevin E, Strickler JH, Weekes CD, et al. Phase I study of ABBV-399, a c-Met antibody-drug conjugate (ADC), as monotherapy and in combination with erlotinib in patients (pts) with non-small cell lung cancer (NSCLC). J Clin Oncol. 2017;35:2509.
Ott PA, Pavlick AC, Johnson DB, et al. A phase II study of glembatumumab vedotin (GV), an antibody-drug conjugate (ADC) targeting gpNMB, in advanced melanoma. J Clin Oncol. 2017;35:109.
Calvo E, Cleary JM, Moreno V, et al. Preliminary results from a phase 1 study of the antibody-drug conjugate ABBV-221 in patients with solid tumors likely to express EGFR. J Clin Oncol. 2017;35:2510.
O'Malley DM, Moore KN, Vergote I, et al. Safety findings from FORWARD II: a phase 1b study evaluating the folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC) mirvetuximab soravtansine (IMGN853) in combination with bevacizumab, carboplatin, pegylated liposomal doxorubicin (PLD), or pembrolizumab in patients (pts) with ovarian cancer. J Clin Oncol. 2017;35:5553. CrossRef
Petrylak DP, Perez RP, Zhang J, et al. A phase I study of enfortumab vedotin (ASG-22CE; ASG-22ME): updated analysis of patients with metastatic urothelial cancer. J Clin Oncol. 2017;35:106.
Pazdur R. Inotuzumab ozogamicin (Besponsa) approval letter. In: Drug approvals and Databases. U.S. Food and Drug Administration, Center for Drug Evaluation and Research. 2017. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2017/761040Orig1s000ltr.pdf. Accessed 3 October 2017.
Horwitz SM, Fanale MA, Spira AI, et al. Interim data from the first clinical study of ADCT-301, a novel pyrrolobenzodiazapine-based antibody drug conjugate, in relapsed/refractory Hodgkin/non-Hodgkin lymphoma. Hematol Oncol. 2017;35:270–1. CrossRef
Almhanna K, Wright D, Mercade TM, et al. A phase II study of antibody-drug conjugate, TAK-264 (MLN0264) in previously treated patients with advanced or metastatic pancreatic adenocarcinoma expressing guanylyl cyclase C. Investig New Drugs. 2017;35:634–41. CrossRef
Gomez-Roca CA, Boni V, Moreno V, et al. A phase I study of SAR566658, an anti CA6-antibody drug conjugate (ADC), in patients (Pts) with CA6-positive advanced solid tumors (STs) (NCT01156870). J Clin Oncol. 2016;34:2511.
Forero A, Burris H III, Mita M, et al. Abstract P3-14-05: interim analysis of a phase 1 study of the antibody-drug conjugate SGN-LIV1A in patients with metastatic breast cancer. Cancer Research. 2016;76:P3–14-05-P13–14-05. CrossRef
Sachdev JC, Maitland M, Sharma M, et al. A phase 1 study of PF-06647020, an antibody-drug conjugate (ADC) targeting protein tyrosine kinase 7 (PTK7), in patients with advanced solid tumors including platinum resistant ovarian cancer (OVCA). Ann Oncol. 2016;27:LBA35.
Garrido-Laguna I, Krop IE, Burris H, et al. A phase I study of PF-06647263, a novel EFNA4-ADC, in patients with metastatic triple negative breast cancer. J Clin Oncol. 2017;35:2511.
Kogawa T, Yonemori K, Naito Y, et al. Phase 1/2, multicenter, non-randomized, open-label, multiple-dose first-in-human study of U3-1402 (anti-HER3 antibody drug conjugate) in subjects with HER3-positive metastatic breast cancer. J Clin Oncol. 2017;35:TPS1116.
Lassen UN, Ramalingam SS, Lopez JS, et al. GCT1021-01, a first-in-human, open-label, dose-escalation trial with expansion cohorts to evaluate safety of Axl-specific antibody-drug conjugate (HuMax-Axl-ADC) in patients with solid tumors (NCT02988817). J Clin Oncol. 2017;35:TPS2605.
Bryan WW. Kymriah (tisagenlecleucel) approval letter. In: Drug approvals and Databases. U.S. Food and Drug Administration, Center for Drug Evaluation and Research. 2017. https://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/UCM574106.pdf. Accessed 2 September 2017.
Papa S, Adami A, Metoudi M, et al. Abstract CT118: T4 immunotherapy of head and neck squamous cell carcinoma using pan-ErbB targeted CAR T-cells. Cancer Res. 2017;77:CT118. CrossRef
Stefanski J, Brentjens R, Hollyman D, et al. CD19-targeted normal and CLL patient T cells expanded with beads can eradicate systemic tumors in vivo. Mol Ther. 2006;13:S102. CrossRef
Park JH, Rivere I, Wang X, et al. Abstract CT078: impact of disease burden and transplant on long-term survival after CD19 CAR therapy in adults with relapsed B-cell acute lymphoblastic leukemia. Cancer Res. 2017;77:CT078. CrossRef
Locke FL, Neelapu SS, Bartlett NL, et al. Clinical and biologic covariates of outcomes in ZUMA-1: a pivotal trial of axicabtagene ciloleucel (axi-cel; KTE-C19) in patients with refractory aggressive non-Hodgkin lymphoma (r-NHL). J Clin Oncol. 2017;35:7512.
Xia L, Chen Q, Li Q, et al. Abstract CT041: the clinical study on CD19-directed chimeric antigen receptor-modified T cells in patient with Richter syndrome. Cancer Res. 2017;77:CT041. CrossRef
Turtle CJ, Hanafi L-A, Berger C, et al. Rate of durable complete response in ALL, NHL, and CLL after immunotherapy with optimized lymphodepletion and defined composition CD19 CAR-T cells. J Clin Oncol. 2016;34:102.
Fan F, Zhao W, Liu J, et al. Durable remissions with BCMA-specific chimeric antigen receptor (CAR)-modified T cells in patients with refractory/relapsed multiple myeloma. J Clin Oncol. 2017;35:LBA3001. CrossRef
Li WP, Guo LJ, Ekaterina M, et al. Immunotherapy of hepatocellular carcinoma with T cells engineered to express glypican-3-specific chimeric antigen receptors. Mol Ther. 2015;23:S164–5. CrossRef
Zhai B, Shi D, Gao H, et al. A phase I study of anti-GPC3 chimeric antigen receptor modified T cells (GPC3 CAR-T) in Chinese patients with refractory or relapsed GPC3+ hepatocellular carcinoma (r/r GPC3+ HCC). J Clin Oncol. 2017;35:3049.
Wang Y, Chen M, Wu Z, et al. CD133-redirected chimeric antigen receptor engineered autologous T-cell treatment in patients with advanced and metastatic malignancies. J Clin Oncol. 2017;35:3042.
Cohen AD, Garfall AL, Stadtmauer EA, et al. B-cell maturation antigen (BCMA)-specific chimeric antigen receptor T cells (CART-BCMA) for multiple myeloma (MM): initial safety and efficacy from a phase I study. Blood. 2016;128:1147.
Berdeja JG, Lin Y, Raje NS, et al. First-in-human multicenter study of bb2121 anti-BCMA CAR T-cell therapy for relapsed/refractory multiple myeloma: updated results. J Clin Oncol. 2017;35:3010. CrossRef
Guo B, Chen M, Han Q, et al. CD138-directed adoptive immunotherapy of chimeric antigen receptor (CAR)-modified T cells for multiple myeloma. J Cellular Immunotherapy. 2016;2:28–35. CrossRef
Falini B, Pileri S, Pizzolo G, et al. CD30 (Ki-1) molecule: a new cytokine receptor of the tumor necrosis factor receptor superfamily as a tool for diagnosis and immunotherapy. Blood. 1995;85:1–14. PubMed
Mackall C, Tap WD, Glod J, et al. Open label, non-randomized, multi-cohort pilot study of genetically engineered NY-ESO-1 specific NY-ESO-1c259t in HLA-A2+ patients with synovial sarcoma (NCT01343043). J Clin Oncol. 2017;35:3000.
Hinrichs CS, Doran SL, Stevanovic S, et al. A phase I/II clinical trial of E6 T-cell receptor gene therapy for human papillomavirus (HPV)-associated epithelial cancers. J Clin Oncol. 2017;35:3009.
Hong DS, Butler MO, Sullivan RJ, et al. A phase I single arm, open label clinical trial evaluating safety of MAGE-A10c796T in subjects with advanced or metastatic head and neck, melanoma, or urothelial tumors (NCT02989064). J Clin Oncol. 2017;35:TPS3098.
Goff SL, Dudley M, Citrin DE, et al. A randomized, prospective evaluation comparing intensity of lymphodepletion prior to adoptive transfer of tumor infiltrating lymphocytes for patients with metastatic melanoma. J Clin Oncol. 2016;34:3006. CrossRef
Noonan KA, Huff CA, Davis J, et al. Adoptive transfer of activated marrow-infiltrating lymphocytes induces measurable antitumor immunity in the bone marrow in multiple myeloma. Sci Transl Med. 2015;7:288ra278. CrossRef
Andtbacka RHI, Curti B, Hallmeyer S, et al. Phase II CALM extension study: enhanced immune-cell infiltration within the tumour micro-environment of patients with advanced melanoma following intralesional delivery of coxsackievirus A21. Eur J Cancer. 2015;51:S677. CrossRef
Pandha HS, Ralph C, Harrington K, et al. Keynote-200 phase 1b: a novel combination study of intravenously delivered coxsackievirus A21 and pembrolizumab in advanced cancer patients. J Clin Oncol. 2017;35:TPS3108.
Silk AW, Kaufman H, Gabrail N, et al. Abstract CT026: phase 1b study of intratumoral coxsackievirus A21 (CVA21) and systemic pembrolizumab in advanced melanoma patients: interim results of the CAPRA clinical trial. Cancer Res. 2017;77:CT026. CrossRef
Curti BD, Richards JM, Hallmeyer S, et al. Activity of a novel immunotherapy combination of intralesional coxsackievirus A21 and systemic ipilimumab in advanced melanoma patients previously treated with anti-PD1 blockade therapy. J Clin Oncol. 2017;35:3014.
Bernstein V, Ellard S, Dent SF, et al. Abstract CT131: a randomized (RCT) phase II study of oncolytic reovirus (pelareorep ) plus standard weekly paclitaxel (P) as therapy for metastatic breast cancer (mBC). Cancer Res. 2017;77:CT131. CrossRef
Alonso MM, García-Moure M, Gonzalez-Huarriz M, et al. Abstract CT027: oncolytic virus DNX-2401 with a short course of temozolomide for glioblastoma at first recurrence: clinical data and prognostic biomarkers. Cancer Res. 2017;77:CT027. CrossRef
Morgensztern D, Harb W, Schalper K, et al. MA09.06 Viagenpumatucel-L bolsters response to nivolumab therapy in advanced lung adenocarcinoma: preliminary data from the DURGA trial. J Thorac Oncol. 2017;12:S394–5. CrossRef
Gray JE, Chiappori A, Williams CC, et al. Phase I/II randomized trial of GM.CD40L vaccine plus/minus CCL21 in advanced lung adenocarcinoma: Final results. J Clin Oncol. 2016;34:9037.
Jabulowsky RA, Loquai C, Diken M, et al. Abstract CT032: a first-in-human phase I/II clinical trial assessing novel mRNA-lipoplex nanoparticles for potent cancer immunotherapy in patients with malignant melanoma. Cancer Res. 2016;76:CT032. CrossRef
Schmitz-Winnenthal FH, Podola L, Hohmann N, et al. A phase 1 trial extension to assess immunologic efficacy and safety of prime-boost vaccination with VXM01, an oral T cell vaccine against VEGF-receptor 2, in patients with advanced pancreatic cancer. J Clin Oncol. 2016;34:3091.
Shore ND, Heath EI, Nordquist LT, et al. A clinical trial for the safety and immunogenicity of a DNA-based immunotherapy in men with biochemically (PSA) relapsed prostate cancer. J Clin Oncol. 2017;35:e14634.
Teixeira L, Medioni J, Doucet L, et al. Results of a first-in-human phase I study of INVAC-1, an optimized plasmid DNA encoding an inactive form of human telomerase reverse transcriptase (hTERT), in patients with advanced solid tumors. J Clin Oncol. 2017;35:3087.
Ghamande SA, Platt D, Wheatley D, et al. Phase I study evaluating high-dose treatment with ADXS11-001, a Listeria monocytogenes-listeriolysin O (Lm-LLO) immunotherapy, in women with cervical cancer. J Clin Oncol. 2016;34:e14580.
Jonker DJ, Hotte SJ, Abdul Razak AR, et al. Phase I study of oncolytic virus (OV) MG1 maraba/MAGE-A3 (MG1MA3), with and without transgenic MAGE-A3 adenovirus vaccine (AdMA3) in incurable advanced/metastatic MAGE-A3-expressing solid tumours: CCTG IND.214. J Clin Oncol. 2017;35:e14637.
Peace KM, Vreeland TJ, Clifton GT, et al. Abstract CT036: early trial results of an autologous tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine in ovarian cancer patients. Cancer Res. 2017;77:CT036. CrossRef
Wood LV, Roberson BD, Agarwal PK, et al. Association of autologous AdHER2 dendritic cell vaccination with antitumor activity and number of circulating tumor cells. J Clin Oncol. 2017;35:3089. CrossRef
Pollack S, Lu H, Somaiah N, et al. Association of CMB305 or LV305-induced and baseline anti-NY-ESO-1 immunity with survival in recurrent cancer patients. J Clin Oncol. 2017;35:3090.
Nishida S, Ishikawa T, Kokura S, et al. Randomized phase II study of WT1 peptide vaccine plus gemcitabine for advanced pancreatic ductal adenocarcinoma (PDAC): clinical efficacy and immune response. J Clin Oncol. 2016;34:3085. CrossRef
Villella JA, Wilson MK, Berinstein NL, et al. Determination of optimal dose and treatment schedule of the immunotherapeutic vaccine, DPX-Survivac, for combination immunotherapy treatment of ovarian, fallopian tube or peritoneal cancer (OC): a phase Ib study. J Clin Oncol. 2016;34:e14577.
Peace KM, Mittendorf EA, Perez SA, et al. Subgroup efficacy evaluation of the AE37 HER2 vaccine in breast cancer patients in the adjuvant setting. J Clin Oncol. 2017;35:3088.
Matsui H, Hazama S, Tamada K, et al. A phase I study of novel multi-HLA-binding peptides and a new combination of immune adjuvants against solid tumors. J Clin Oncol. 2017;35:3086. CrossRef
Yasuda T, Nishiki K, Yoshida K, et al. Cancer peptide vaccine to suppress postoperative recurrence in esophageal SCC patients with induction of antigen-specific CD8+ T cell. J Clin Oncol. 2017;35:e14635.
Yamaue H, Miyazawa M, Katsuda M, et al. Phase II clinical trial using novel peptide vaccine cocktail as a postoperative adjuvant treatment for surgically resected pancreatic cancer patients. J Clin Oncol. 2016;34:e14587. CrossRef
Slingerland M, Speetjens F, Welters M, et al. A phase I study in patients with a human papillomavirus type 16 positive oropharyngeal tumor treated with second generation synthetic long peptide vaccine conjugated to a defined adjuvant. J Clin Oncol. 2016;34:TPS3113. CrossRef
Kyi C, Sabado RL, Saenger YM, et al. In situ, therapeutic vaccination against refractory solid cancers with intratumoral poly-ICLC: a phase I study. J Clin Oncol. 2016;34:3086.
Marquez Rodas I, Rodriguez-Ruiz ME, Lopez-Tarruella S, et al. First-in-human clinical trial with intratumoral BO-112 in solid malignancies: a novel immunotherapy based in double-stranded RNA (dsRNA). J Clin Oncol. 2017;35:3082.
Forero A, Bendell JC, Kumar P, et al. First-in-human study of the antibody DR5 agonist DS-8273a in patients with advanced solid tumors. Investig New Drugs. 2017;35:298–306. CrossRef
Chiocca EA, Yu J, Phuphanich S, et al. Expanded phase I study of intratumoral Ad-RTS-hIL-12 plus oral veledimex: tolerability and survival in recurrent glioblastoma. J Clin Oncol. 2017;35:2044. CrossRef
Diab A, Tannir NM, Bernatchez C, et al. A phase 1/2 study of a novel IL-2 cytokine, NKTR-214, and nivolumab in patients with select locally advanced or metastatic solid tumors. J Clin Oncol. 2017;35:e14040.
Bernatchez C, Haymaker CL, Hurwitz ME, et al. Effect of a novel IL-2 cytokine immune agonist (NKTR-214) on proliferating CD8+T cells and PD-1 expression on immune cells in the tumor microenvironment in patients with prior checkpoint therapy. J Clin Oncol. 2017;35:2545.
Siu LL, Gelmon K, Chu Q, et al. Abstract CT116: BMS-986205, an optimized indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor, is well tolerated with potent pharmacodynamic (PD) activity, alone and in combination with nivolumab (nivo) in advanced cancers in a phase 1/2a trial. Cancer Res. 2017;77:CT116. CrossRef
Zakharia Y, Drabick JJ, Khleif S, et al. Updates on phase1b/2 trial of the indoleamine 2,3-dioxygenase pathway (IDO) inhibitor indoximod plus checkpoint inhibitors for the treatment of unresectable stage 3 or 4 melanoma. J Clin Oncol. 2016;34:3075.
Bahary N, Garrido-Laguna I, Cinar P, et al. Phase 2 trial of the indoleamine 2,3-dioxygenase pathway (IDO) inhibitor indoximod plus gemcitabine/nab-paclitaxel for the treatment of metastatic pancreas cancer: interim analysis. J Clin Oncol. 2016;34:3020. CrossRef
Jha GG, Gupta S, Tagawa ST, et al. A phase II randomized, double-blind study of sipuleucel-T followed by IDO pathway inhibitor, indoximod, or placebo in the treatment of patients with metastatic castration resistant prostate cancer (mCRPC). J Clin Oncol. 2017;35:3066.
Hamid O, Bauer TM, Spira AI, et al. Safety of epacadostat 100 mg bid plus pembrolizumab 200 mg Q3W in advanced solid tumors: phase 2 data from ECHO-202/KEYNOTE-037. J Clin Oncol. 2017;35:3012.
Perez RP, Riese MJ, Lewis KD, et al. Epacadostat plus nivolumab in patients with advanced solid tumors: preliminary phase I/II results of ECHO-204. J Clin Oncol. 2017;35:3003.
Gupta S, Grilley-Olson J, Hong D, et al. Abstract CT091: safety and pharmacodynamic activity of MEDI9197, a TLR 7/8 agonist, administered intratumorally in subjects with solid tumors. Cancer Res. 2017;77:CT091. CrossRef
Dredge K, Brennan T, Brown MP, et al. An open-label, multi-center phase I study of the safety and tolerability of the novel immunomodulatory agent PG545 in subjects with advanced solid tumors. J Clin Oncol. 2017;35:3083. CrossRef
de la Torre AN, Contractor S, Castaneda I, et al. A phase I trial using local regional treatment, nonlethal irradiation, intratumoral and systemic polyinosinic-polycytidylic acid polylysine carboxymethylcellulose to treat liver cancer: in search of the abscopal effect. J Hepatocell Carcinoma. 2017;4:111–21. PubMedPubMedCentralCrossRef
Papadopoulos KP, Tsai FY-C, Bauer TM, et al. CX-1158-101: a first-in-human phase 1 study of CB-1158, a small molecule inhibitor of arginase, as monotherapy and in combination with an anti-PD-1 checkpoint inhibitor in patients (pts) with solid tumors. J Clin Oncol. 2017;35:3005.
Spicer JF, Baurain J-F, Awada A, et al. LTX-315, an oncolytic peptide, to convert immunogenically ‘cold’ tumors to ‘hot’ in patients with advanced or metastatic tumours: results from an ongoing phase I study. J Clin Oncol. 2017;35:3085. CrossRef
- Cancer immunotherapy beyond immune checkpoint inhibitors
Julian A. Marin-Acevedo
Aixa E. Soyano
Keith L. Knutson
- BioMed Central
Neu im Fachgebiet Onkologie
Mail Icon II