The importance of correctly timing cancer immunotherapy

Figures & data

Table 1. Classification of different combinatorial strategies based on timing regimen and mechanism.

Timing of the intervention		Intervention	Cancer type	Combined treatment regimen	Efficacy/immunological responses of combined treatments	Mechanisms of intervention		References
Prior to treatment	8 weeks before vaccine	Carboplatin + cisplatin	Extensive stage small cell lung cancer	P53 DC cancer vaccine + carboplatin + cisplatin	High rate of objective clinical responses Association of clinical response with immunologic response	No proposed mechanism	Counteracting suppressive immunity by reducing immunosuppressive cells	Antonia et al. [46]
	2 weeks before vaccine	Carboplatin + paclitaxel	Advanced ovarian cancer	Tumor antigen-loaded DCs + carboplatin + paclitaxel	Immune reconstitution Enhanced antitumor immune response	Decreased percentage of Tregs		Wu et al. [47]
	2 weeks before vaccine	Carboplatin + paclitaxel	HPV 16/17 TC-1 tumor model Advanced cervical cancer	HPV16-SLP vaccination + carboplatin + paclitaxel	Decreased immunosuppressive myeloid cells Increased vaccine-induced T-cell response Improved overall survival of mice	Myeloid cells depletion		Welters et al. [48]
	11 days before vaccine	Irradiation	F10 melanoma tumor model	DC-gp100 tumor vaccine + irradiation	Reduced tumor burden and prolonged mouse survival	Decreased Tregs and increase effector-memory T-cells frequency		Liu et al. [49]
	7 days before vaccine	Cyclophosphamide	Stage II-III melanoma cancer	HLA-A*0201-modified tumor peptide vaccine + cyclophosphamide + IL-2	Increased tumor-specific T-cells	Lower frequency of Tregs		Camisaschi et al. [50]
	4 days before vaccine	Cyclophosphamide	Gastrointestinal, lung, cervical and colorectal cancer	HLA-A2402-restricted tumor-associated antigen epitope peptides + cyclophosphamide	Association of prolonged survival with TAA-specific T-cell responses Safety and correlation of immune responses with vaccine-induced T-cell response in phase I clinical trial	Reduced number of Tregs		Murahashi et al. [51]
	3 days before vaccine	Cyclophosphamide	Advanced renal cell cancer	Multiple tumor associated peptides (TUMAPs) + cyclophosphamide	Prolonged survival in immune responders’ patients	Reduced number of Tregs		Walter et al. [52]
	4 and 1 days before treatment	Gemcitabine	Mesothelioma AB12 tumor model	IFN-β cytokine immunogene therapy + gemcitabine	Enhanced antitumor efficacy	Decreased myeloid suppressor cells		Suzuki et al. [53]
	1 day before vaccine	Gemcitabine	Setting without tumor	Particle-mediated epidermal delivery vaccination against NY-ESO-1	Improved the efficacy of vaccine	Reduced percentage of Tregs		Rettig et al. [54]
	4 days before vaccine	Anti-CD25 antibody	B16 melanoma tumor model	Tumor cell-based vaccine + anti-CTLA-4 + anti-CD25	Increased CTL specific response	Depletion of Tregs		Sutmuller et al. [55]
	4 days before prophylactic vaccine	Anti-CD25 antibody	CT26 colorectal carcinoma model	tumor-specific peptide vaccine + anti-CD25	Induction of long-lasting antitumoral immune response	Depletion of Tregs		Casares et al. [56]
	1 day before prophylactic vaccine	Anti-CD25 antibody	B16-F10 tumor model	DC vaccine with stressed tumor cells + anti-CD25	Improved the efficacy of treatment and developed long-lived tumor- protective immune responses	Depletion of Tregs		Prasad et al. [57]
	5 days before ACT and vaccine	PLX3397 kinase inhibitor	B16F10 melanoma tumor model	Adoptive transfer of pmel-1 CD8 T-cells and peptide vaccination + PLX3397 kinase inhibitor	Enhanced CD8-mediated effect of immunotherapy Increase IFNγ- production of tumor-specific CD8^+ T-cells	Inhibits CSF-1 R Decreased tumor infiltrating macrophages		Sluijter et al. [58]
	4 days before ACT	PLX3397 kinase inhibitor	Syngeneic mouse model of BRAF(V600E)-driven melanoma	Adoptive cell therapy + PLX3397 kinase inhibitor	Enhanced anti-tumor response Increased IFNγ- producing tumor-infiltrating lymphocytes	Inhibit CSF-1 R Decreasing tumor-infiltrating myeloid cells Skewing MHCII^low towards MHCII^hi macrophages		Mok et al. [59]
	Prior to vaccination	IL-2 diphtheria toxin conjugate DAB389IL-2	Renal cell carcinoma	Tumor RNA-transfected DC vaccine + IL-2 diphtheria toxin conjugate DAB389IL-2	Improved the stimulation of tumor-specific T-cell response	Deplete Tregs		Dannull et al. [60]
	2 weeks before vaccine	Chemoradiation	Esophageal squamous cell carcinoma	Multiple epitopes peptide vaccine + cisplatin+ 5FU + radiotherapy	Safety in phase I clinical trial Demonstrate peptide-specific CTL responses	Enhancement of the immunogenicity of the cancer cells and antigen presentation of DCs, thereby increasing CTL responses	Improvement of the T-cell response	Iinuma et al. [61]
	3 days before vaccine	Gemcitabine	Advanced pancreatic cancer	Antigen-pulsed DCs + lymphokine-activated killer cells stimulated with anti-CD3 (CD3-LAKS) + gemcitabine	A synergistic antitumor effect	Induction of tumor antigen-specific CTLs		Hirooka et al. [62]
	2 days before vaccine	Docetaxel	Established lewis lung carcinoma model	GM-CSF-producing tumor vaccine + docetaxel	Tumor regression and prolonged survival	Enhanced survival of antigen-experienced cells Reduced pre-existing memory cells Decreased Tregs		Chu et al. [63]
	2 days before vaccine	Radiation	HPV 16/17 TC-1 tumor model	DNA vaccine encoding calreticulin liked to HPV-E7 + radiation	Induction of antitumor effect Improved survival of tumor-bearing mice Increased E7-specific tumor-infiltrating CD8^+ T-cells	Enhancement of tumor cell apoptosis by radiotherapy Increased cell-mediated lysis of tumor cells		Tseng et al. [64]
	1 day before ACT	Cyclophosphamide	Friend leukemia	Adoptive transfer of lymphomonocytes from tumor-immunized mice + cyclophosphamide	Improved antitumor efficacy	Upregulation of various immunomodulatory factors Induction of Th17, Th1 and activated CD4^+		Moschella et al. [65]
	1 day before vaccine	Cyclophosphamide	Advanced melanoma	NY-ESO-1/ISCONATRIX vaccine + low dose cyclophosphamide	Improved the immunogenicity of the vaccine	Increase vaccine-induced NY-ESO-1-specific CD4^+ T-cell response		Klein et al. [66]
	1 day before vaccine	Cisplatin + 5-FU	MC38 murine colorectal adenocarcinoma tumor model	Intratumoral DCs injection + Low doses of cisplatin + 5-FU	Complete rejection and prolonged survival	Increase cytolytic activity of effector tumor-specific CD8^+ T-cells		Tanaka et al. [67]
	1 day before vaccine	Dacarbazine	Melanoma	Vaccine consisting HLA-A2 restricted melanoma antigen A and gp100 analog peptide + dacarbazine	Improved long-lasting memory CD8^+ T-cell response	Dacarbazine -induced gene activation involved in cytokine production, Leukocyte activation, immune response and cell motility Widening of TCR repertoire diversity with high avidity and tumor reactivity		Nistico et al. [68] Palermo et al. [69]
	1 day before vaccine	Cisplatin	HPV 16/17 TC-1 tumor model	HPV16 E6E7L2 fusion protein (TA-CIN) with GPI-0100 adjuvant + cisplatin	Reduced tumor out growth and extended survival	Induced tumor antigen-specific CD8^+ T-cells		Peng et al. [70]
	5 h before ACT	Cyclophosphamide	Murine lymphomas	Adoptive transfer of tumor-immune cells + cyclophosphamide	Enhanced the antitumor efficacy	Migration of tumor-immune lymphocytes to the tumor Promotion of homeostatic proliferation/activation of transferred lymphocytes Cytokine storm induction		Bracci et al. [71]
	7 days before vaccine	Sunitinib	Colon carcinoma (MC38-CEA)	Poxvirus-based vaccine encoding (CEA) plus 3 costimulatory molecules + sunitinib	Reduced tumor volumes Increased survival	Increased intratumoral infiltration of antigen-specific T-cells Improved type-1 T-cell cytokine response Decreased Tregs and MDSCs	Counteracting suppressive immunity by reducing immunosuppressive cells and Improve T-cell response	Farsaci et al. [72] and Finke et al. [73]
	4–7 days before vaccine	Cisplatin	HPV 16/17 TC-1 tumor model	DNA vaccine encoding calreticulin liked to HPV-E7 + cisplatin	Induce significant anti-tumor effect Improved survival of tumor bearing mice Increase E7-specific tumor-infiltrating CD8^+ T-cells	Increased MHC class I expression by tumor cells upon cisplatin treatment Increase cell-mediated lysis of tumor cells Decrease myeloid suppressor cells and Tregs in blood and spleen		Tseng et al. [74]
	4 days before vaccine	Cisplatin	HPV 16/17 TC-1 tumor model	Vaccinia vaccine encoding HPV-16 E7 + cisplatin	Induce significant anti-tumor effect Increase E7-specific tumor-infiltrating CD8^+ T-cells	Increase intratumoral CD11c^+ Decrease myeloid suppressor cells in spleen		Lee et al. [75]
In combination	Concurrent with vaccine	Cyclophosphamide	Advanced ovarian cancer	Surviving HLA class I peptides (DPX-survivac) + metronomic cyclophosphamide	Enhanced T-cell response associated with differentiation of naïve T-cells into central/effector memory and late differentiated polyfunctional antigen-specific T-cells	Enhanced vaccine induced T-cell response	Improvement of the T-cell response	Berinstein et al. [76]
	1 day before vaccine (cyclophosphamide + paclitaxel) and 1 week after vaccine (doxorubicin)	Cyclophosphamide + Paclitaxel + doxorubicin	Mammary tumor model in antigen-specific tolerized neu transgenic mice	GM-CSF-secreting HER-2/neu(neu)-expressing whole-cell vaccine + cyclophosphamide + paclitaxel + doxorubicin	Enhanced vaccine anti-tumor effect to delay tumor growth	Enhanced the efficacy of vaccine Increased neu-specific T-cells and Th1 response		Machiels et al. [77]
	Concurrent with vaccine	CD27 antibody	Prostate cancer model	Tumor lysate-pulsed DC vaccine + CD27 antibody	Reduced tumor outgrowth	Enhanced T-cell response		Wei et al. [78]
	Concurrent with vaccine	Cyclophosphamide + Paclitaxel + docetaxel	Hepatocellular carcinoma patients	Multi-peptide cocktail including HCV and tumor antigen vaccine + cyclophosphamide + paclitaxel + docetaxel	Enhanced specific T-cell response	Reduced Treg frequency	Counteracting suppressive immunity by reducing immunosuppressive cells	Tagliamonte et al. [79]
	Concurrent with vaccine	Gemcitabine	Platinum-resistant ovarian cancer	p53 SLP vaccine + pegilated IFN-α + gemcitabine	Safe, feasible, immune stimulatory effect of combined treatment	Reduction in MDSCs by gemcitabine and increase in M1 macrophages		Dijkgraaf et al. [80]
	Concurrent with vaccine	Cisplatin	HPV 16/17 TC-1 tumor model	HPV16-SLP vaccination + cisplatin	A synergistic antitumor effect	Sensitize tumor cells to cisplatin-mediated death by TNFα produced by tumor-specific T-cells	Increased tumor cell apoptosis	Van der Sluis et al. [81]
	Concurrent with vaccine	Nivolumab	Resected stage IIIC and IV melanoma	Tumor antigen multi-peptide vaccine + nivolumab	Demonstrated immunologic activity with promising survival	Increased tumor-specific CD8^+ T-cells but also CTLA-4^+ CD4^+ and CD25^+ Tregs	Counteracting inhibitory immune regulation	Gibney et al. [82]
	Concurrent with vaccine	Anti-PD-1	B16 melanoma	IFNγ-inducing cancer vaccine combined with GM-CSF + TLR agonists + anti-PD-1	Complete tumor regression	Blocking the inhibitory effect of PD-1 induced by vaccine		Fu et al. [83]
	Concurrent with vaccine	Anti-PD-1	Advanced or metastatic HCC patients And RMA lymphoma tumor model	Peptide vaccine + anti-PD-1	Increased tumor specific CTL number and response Synergistic tumor outgrowth reduction	Blocking the PD-1 signaling induced by vaccine on specific CTL Increased TILs and decreased inhibitory receptor on TILs		Sawada et al. [84]
	Concurrent with vaccine	Anti PD-1	TC-1 HPV16/17 tumor model	Listeria monocytogenes based vaccine expressing HPV16 E7 + anti PD-1	Tumor outgrowth inhibition and prolonged survival	Increased Teff/Tregs ratio Increased tumor-specific T-cell response by blocking PD-1/PD-L1 pathway as PD-L1 induced by vaccine		Mkrtichyan et al. [85]
	Concurrent with vaccine	Anti-CTLA-4	Prostate tumor model	GM-CSF-secreting vaccine (GVAX) + anti-CTLA-4	Increased tumor-specific cells and lytic function	Blocking the inhibitory effect of CTLA-4 induced by vaccine on tumor specific CD8^+ T-cells		Wada et al. [86]
	Concurrent with vaccine	Anti-IL10R1 monoclonal antibody	Bladder tumor model	Bacillus Calmette-Guérin vaccine + anti-IL10R1 monoclonal antibody	Enhanced anti-bladder cancer immunity and prevention metastasis to lung	Increased CTL specific response	Counteracting suppressive immunity induced by tumor or immunotherapy	Newton et al. [87]
After	1 day after vaccine	Anti- 4–1BB	MCA205 and MCA207 fibrosarcomas	DC vaccine pulsed with tumor lysate + anti-4–1BB	Enhanced tumor regression and improve survival	Increased costimulatory signal of 4-1BB enhanced by vaccine on NK, CD4 and CD8 T-cells Increased T-cell response	Increased costimulatory signals to improve T-cell function	Ito et al. [88]
	2 days after vaccine	Anti-OX40 + anti-4-1-BB	Mammary carcinoma (N202.1A tumor cells in Her-2/neu mice)	DC vaccine pulsed with apoptotic tumor cells + anti-OX40 + anti-4-1-BB	Tumor reduction and rejection	Enhanced CD4 and CD8 T-cell response		Cuadros et al. [89]
	1 day after vaccine	SM16 (TGFβ blockade)	TC-1 HPV16/17 tumor model	Adenovirus expressing HPV-E7 + SM16	Delayed the tumor outgrowth Increase intratumoral leukocyte infiltration Increase intratumoral antigen-specific CD8^+ T-cells	Increased immunostimulatory cytokines and ICAM-1 Increased the percentage and functional status of CD8^+ T-cells	Improvement of the T-cell response	Kim et al. [90]
	3–6 days after vaccine	Radiation	Colon adenocarcinoma tumor cells expressing CEA (MC38-CEA)	Recombinant vaccinia/avipox CEA-TRICOM vaccine + radiation	Significant Tumor eradication	Upregulation of Fas on tumor cells by radiation Increased infiltration of T-cells to tumor Induced tumor-specific T-cell response	Induced tumor cell apoptosis and improved T-cell response	Chakraborty et al. [91]
	5 days after vaccine	Radiation	HPV-associated head and neck squamous cell carcinoma	Shiga Toxin B-based HPV vaccine + radiation	Complete tumor clearance	Increased tumor-infiltrating antigen-specific T-cells Induced CD8^+ T-cell memory Enhanced intratumoral vascular permeability	Enhanced intratumoral vascular permeability and improved T-cell response	Mondini et al. [92]

ACT: adoptive cell transfer; CEA: carcinoembryonic antigen; CTLA-4: cytotoxic T-lymphocyte-associated protein 4; CTL: cytotoxic T lymphocytes; CSF-1 R: colony stimulating factor-1 receptor; DC: dendritic cell; GM-CSF: granulocyte-macrophage colony-stimulating factor; gp100: glycoprotein 100; HPV: human papillomavirus; HLA: human leukocyte antigen; HER-2: human epidermal growth factor receptor 2; HCV: hepatitis C virus; HCC: hepatocellular carcinoma; IL-2: interleukin-2; IFN-α: interferon-alpha; IFN-β: interferon beta; IFNγ: interferon gamma; IL-10R1: interleukin 10 receptor 1; MHC: major histocompatibility complex; MDSCs: myeloid-derived suppressor cells; NK: natural killer cells; PD-1: programmed cell death protein 1; PD-L1: programmed death-ligand 1; RNA: ribonucleic acid; SLP: synthetic long peptide; Tregs: regulatory T-cells; TAA: tumor-associated antigens; TDLN: tumor-draining lymph node; Th: T helper cells; TCR: T-cell receptor; TLR: Toll-like receptor; TILs: tumor-infiltrating lymphocytes; TNF-α: tumor necrosis factor alpha.

Figure 1. Illustration of different timing schedules of various therapies in combination with immunotherapy based on their mechanisms. The individual examples of each combination therapy are summarized in Table 1. The colour gradients show the time points (prior, concurrent and/or after immunotherapy) at which the therapies are mostly applied. The blue box shows the therapies which are mostly applied prior to immunotherapy and less often concurrent with immunotherapy. The orange box shows the therapies which are often applied concurrent with immunotherapy and less after immunotherapy. The green box shows the therapies which are used mainly after immunotherapy and less concurrent with immunotherapy. Abbreviations: Tregs: Regulatory T-cells, MDSC: Myeloid-derived suppressor cells, M2 macrophages: type 2 macrophages, DC: dendritic cell.

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