Fig 1.
Multiscale flow diagram of immunogenicity to cancer vaccine.
The immunological mechanism starts when a patient receives a cancer vaccine, a combination of immunogenic peptides and adjuvant. Adjuvant helps enhance the maturation of immature DCs for antigen presentation at the mature DC surface. Endocytosed peptides interact with MHC-I/II molecules at the subcellular level in matured DCs through binding, dissociating or degradation. Subsequently, antigen-specific T cells are activated by peptides bound to MHC-I/II. Only activated CD8+ T cells can kill tumor cells. Nonetheless, activated CD4+ T cells can help activate CD8+ by tumor stimulation or secretion of IL-2. The solid (dashed) arrows indicate direct (indirect) interactions between the populations at the cellular or subcellular level. The dotted arrows indicated interactions between populations at the subcellular and cellular levels. (APCs: Antigen presenting cells, TCR: T cell receptors. j and k determine the number of specific MHC-I/II allelic molecules.
Table 1.
Description of model population (or state) variables including units [33].
Fig 2.
Patient-specific initial conditions are the values of all population variables in Table 1 at the start of the treatment. Patient-specific parameters are T cell recruitment and tumor killing rates, while neoantigen-specific parameters refer to unique immunogenic peptide sequences and binding affinities tailored to each patient. All these values can be found in Tables A and B in S1 Appendix.
Fig 3.
Optimal peptide dose selection.
Selecting the predicted optimal peptide dose with higher clinical benefit in overall tumor reduction than the tested vaccine dose. Blue and Red curves correspond to J and JT scores as a function of the predicted optimal doses, . Horizontal lines indicate the J and JT scores of tested dose,
. Red region includes suboptimal doses. Blue region offers doses with potential clinical benefit. Doses below the blue dashed line are optimal with uncertain clinical benefit. Doses between dashed lines are optimal with lower clinical benefit. Doses in the green region are optimal, with a higher benefit in tumor reduction.
Table 2.
Peptide dose and adjuvant:peptide ratio converted from clinical trial data for patients with melanoma [33].
Fig 4.
Tumor diameter on day 200 as function of constant peptide concentration on each vaccination day.
Vertical lines correspond to the lower and upper bounds set for this dose optimization study for the amount of peptides as the log-folds of the clinical trial dose. The red and green areas indicate tumor growth and reduction from the initial tumor size, respectively.
Fig 5.
Optimal peptide concentrations.
Bar plots correspond to optimal peptide doses as the number of folds of the clinical trial dose for each vaccination using J1 (blue) and J2 (green). The horizontal dashed line represents the dose used in the clinical trial (baseline) given in Table 2 for each patient. The total number of immunizing peptides is also reported at the top of each panel. The weights for J1 are A1 = 1 and B = 1/3, while for J2 the weights are A1 = 1, A2 = 1 and B = 1.
Fig 6.
Activated T-cells (ACD4 + ACD8) when optimal (blue and green solid curves, respectively) and suboptimal (dashed, solid and dotted orange are 3, 1, 0.1 folds of clinical trial dose, respectively) vaccine doses are applied to each patient using J1 and J2. Red dots represent patients’ measurements at specific times in the clinical trial with 15% standard error. The vertical green dashed lines correspond to the days of vaccination.
Fig 7.
Tumor diameter when optimizing J1 and J2, and optimal (blue and green curves), suboptimal (dotted, solid, and dashed orange are 3, 1, and 0.1 folds of clinical trial dose, respectively) and no (red) vaccinations are applied. Numbers with an arrow are pointing at the blue curve when t = 200 days, represent the tumor diameter at the end of the treatment (from J1). The vertical green dashed lines correspond to the days of vaccination.
Table 3.
Optimal vaccine dose performance using overall and individual ratios for J1 together with total vaccine dose ratio when compared to clinical trial dose. Green cells indicate more clinical benefit or a lower total vaccine dose. Red cells indicate less clinical benefit or a higher total vaccine dose.
Table 4.
Optimal vaccine dose performance using overall and individual ratios for J2 together with total vaccine dose ratio when compared to clinical trial dose. Green cells indicate more clinical benefit or a lower total vaccine dose. Red cells indicate less clinical benefit or a higher total vaccine dose.