







































_____________________________________________________________________________________________________ 
 
++ MD/PhD, Senior Faculty of Principal Research Scientist; 
# Alumni Professor; 
*Corresponding author: E-mail: bli@augusta.edu, brli1@juno.com; 
 
Cite as: Li, Shen, and Biaoru Li. 2024. “Optimizing Cancer Immunotherapy through Combination Therapies: Advances in 
Chemoimmunotherapy, Lymphodepletion, and Precision Medicine”. Asian Journal of Immunology 7 (1):247-57. 
https://journalaji.com/index.php/AJI/article/view/148. 
 

 
 

Asian Journal of Immunology 
 
Volume 7, Issue 1, Page 247-257, 2024; Article no.AJI.126682 
 

 
 

 

 

Optimizing Cancer Immunotherapy 
through Combination Therapies: 

Advances in Chemoimmunotherapy, 
Lymphodepletion, and Precision 

Medicine 
 

Shen Li a++ and Biaoru Li b,c++#* 
 

a University of Chicago Medical Center, Section of General Surgery, Chicago, IL 60637, USA. 
b Department of Pediatrics and GA Cancer Center, Children Hospital at GA, Augusta, GA 30913, 

Georgia.  
c School of Medicine, CWRU, 10900 Euclid Ave, Cleveland, OH 44106, USA. 

 
Authors’ contributions  

 
This work was carried out in collaboration between both authors. Both authors read and approved the 

final manuscript. 
 

Article Information 
 

DOI: https://doi.org/10.9734/aji/2024/v7i1148  
 

Open Peer Review History: 
This journal follows the Advanced Open Peer Review policy. Identity of the Reviewers, Editor(s) and additional Reviewers, peer 

review comments, different versions of the manuscript, comments of the editors, etc are available here: 
https://www.sdiarticle5.com/review-history/126682  

 
 

 

Received: 10/09/2024 
Accepted: 12/11/2024 
Published: 15/11/2024 

 
 

ABSTRACT 
 

Chemoimmunotherapy was a challenge issue in an early clinical study. Cytotoxic chemotherapy 
was immunosuppressive while, in the clinic, chemoimmunotherapy demonstrated supporting 
immunotherapy. To increase ACT (adoptive cell transfer) immunotherapy and decrease the effects 

Review Article 

mailto:bli@augusta.edu
https://doi.org/10.9734/aji/2024/v7i1148
https://www.sdiarticle5.com/review-history/126682


 
 
 
 

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248 

 

of chemotherapy for Tumor-infiltrating lymphocytes (TILs) to treat solid tumors, we began to study 
chemoimmunotherapy by isolating and culturing primary tumor cells and immune cells from the 
removed solid tumor tissues before 1994. After about 30-40 years of efforts, results of optimizing 
combination treatment have demonstrated that chemotherapy combined with immunotherapy 
(called chemoimmunotherapy) is better than monotherapy; now there are four fields to be 
developed for the optimizing combination, including (1) Lymphodepletion (LD) supporting ACT 
immunotherapy for Advanced Cancer, (2) Chemoimmunotherapy (CI) supporting treatment for 
Advanced Cancer, (3) Immune Checkpoint Inhibition (ICI) combined with immunotherapy, and (4) 
Precision Medicine (PM) supporting immunotherapy for Advanced Cancer. Precision therapy can 
cover all three, as described above, as well as LD, chemoimmunotherapy, and ICI combination. 
Techniques for precision therapy include tumor tissue biobanks, single cell technique, clinical 
genomics, and artificial intelligence to support the combination treatment. Overall, the latest 
generation of optimizing combination therapies is more specific and sensitive in treating neoplastic 
diseases than older versions with fewer side effects. Based on 30–40 years of R&D to improve 
immunotherapy for patients with advanced cancer and based on increasing research, it is time to 
define combinations treatment and evaluate the efficacy of optimizing combination treatments for 
oncological diseases 
 

 

Keywords: Cancer; chemoimmunotherapy; cytotoxic chemotherapy; oncological diseases. 
 

1. INTRODUCTION  
 
In 1986, Dr. Rosenberg discovered that isolated 
and cultured Tumor-infiltrating lymphocytes (TILs) 
from tumor tissue could be applied to the 
adoptive cell transfer (ACT) to treat advanced 
melanoma [1]. In addition, they also used a 
combined CTX before TIL infusion therapy for 
the treatment of tumor patients so that CTX could 
eliminate lymphocytes in vivo to support ACT 
immunotherapy [2]. Lymphodepletion (LD) is 
routinely used in ACT immunotherapy, such as 
CAR-T and TIL therapy [3-4]. After about four 
decades of efforts, some research on 
combination therapy has demonstrated that 
chemotherapy coordinating with             
immunotherapy (called chemoimmunotherapy) is                                
better than monotherapy; however, 
understanding regimens of combination therapy 
also includes chemotherapeutic drugs,                  
optimal drug dose, administration time, and 
sequence of chemoimmunotherapy is still not 
clear [5-6]. 
 
We have discovered the “confused phenomenon” 
in our early study. To address the phenomenon, 
we began to study both tumor cells and immune 
cells from the removed same solid tumor tissues, 
which were published in 1994 [7]. We aimed to 
increase TIL ACT efficacy and decrease 
chemotherapy toxicity to ACT immunotherapy at 
that time. Our strategies included that both TIL 
and primary tumor cells culture from the solid 
tumor tissues so that the cultured TILs from solid 
tumors are activated and then infused into 
patients for ACT immunotherapy. “At the same 

time, the primary tumor cells from the tumor 
tissues are utilized as in vivo and in vitro 
chemosensitivity tests for specific chemotherapy 
drugs to decrease chemotherapy toxicity to ACT 
immunotherapy. As our early report for 
combination therapy for patients with solid 
tumors by TIL re-infusion and chemotherapy 
using an in vitro chemosensitivity test, we 
discovered the combination was better than the 
monotherapy. Following thirty years of research 
for combination treatment, we have developed 
precision medicine, including tumor tissue 
biobanks, single cell technique, clinical genomics, 
and artificial intelligence to support the 
combination treatment. Overall, the latest 
generation of combination therapies is more 
specific and sensitive in treating neoplastic 
diseases than older versions with fewer side 
effects” [8-12]. 
 
Based on 30–40 years of R&D to improve 
immunotherapy for patients with advanced 
cancer and based on increasing research, it is 
time to define combinations treatment and 
evaluate the efficacy of combination treatments 
for oncological diseases. According to the current 
publications, the manual will introduce four 
sections for optimizing combination therapy: (1) 
Lymphodepletion (LD) supporting ACT 
immunotherapy for Advanced Cancer, (2) 
Coordinated Therapy (Chemoimmunotherapy) 
supporting treatment for Advanced Cancer, (3) 
Immune Checkpoint Inhibition (ICI) combined 
with immunotherapy, and (4) Precision           
Medicine supporting Immunotherapy for 
Advanced Cancer. 



 
 
 
 

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2. LYMPHODEPLETION SUPPORTING 
ACT IMMUNOTHERAPY TO TREAT 
ADVANCED CANCER 

 
Over the past 40 years, adoptive cell transfer 
(ACT) for the treatment of malignancies has 
been one of the most dynamic and fruitful 
advances in cancer therapy [13-14]. To support 
ACT efficacy, in 1986, Dr. Rosenberg first used 
CTX as Lymphodepletion (LD) to support the TIL 
reinfusion for overcoming immune tolerance in 
patients with metastatic melanoma [15]. Other 
solid tumor diseases have also routinely used LD 
to support TIL reinfusion in clinics [16-17], as 
shown in Fig. 1. Moreover, CAR-T (chimeric 
antigen receptors) has become an essential 
antitumor therapy component [18]. However, a 
significant number of these patients still relapse 
after CAR-T therapy or become resistant to CAR-
T therapy [19-20], so they need to improve the 
efficacy of CAR-T therapy by LD to play an 

essential role in overcoming the resistance to 
CAR-T therapy [21-22].  
 

The main goals of LD are to (1) reduce 
endogenous lymphocytes to inhibit the 
engraftment of CAR-T infusions and support their 
long-term activity; (2) reduce tumor cells to avoid 
rapid exhaustion of CAR-Ts; and (3) prepare and 
reprogram the microenvironment and soluble 
factors to ensure optimal engraftment, homing, 
and long-term survival of CAR-T cells [23-25]. As 
in Table 1, there are several LDs, such as 
fludarabine (Flu) and cyclophosphamide (CTX, 
Cy), and their combination is selectively used for 
individual situations. LD regimens and doses 
vary depending on the target disease (such as 
ALL, NHL, MM, or solid tumors) and the source 
of T cells (autologous vs. allogeneic) [26-28]. 
Because a patient receives LD with individual 
differences, personalized regimens still need to 
be considered for LD selection with their doses 
for the new TIL or CAR-T therapy approaches. 

 
 

 
 

Fig. 1. Strategy for LD to increase TIL efficacy 
NB. A lymphodepletion regimens adding TIL treatment to increase TIL efficacy. 

 

Table 1. Lymphodepletion 

Types Components Common 
lymphodepletion  

Common usage 

Fludarabine purine analogue Car-T CLL and indolent NHL 

Cyclophosphamide an alkylating agent TIL or Car-T Melanoma, lymphoma, and 
indolent NHL 

Flu and Cy both action Car-T CALL 

Bendamustine an alkylating agent Car-T CLL and other B- and T-cell 
lymphomas 

Alemtuzumab Targeting  Car-T lymphoproliferative diseases 

Oxaliplatin/cy Targeting  Car-T CAR-T to solid tumors 

Clofarabine anti-leukemic 
agent 

Car-T clinical remission 



 
 
 
 

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3. CHEMOIMMUNOTHERAPY COMBI-
NATIONS SUPPORTING 
IMMUNOTHERAPY 

 
Chemotherapy has been a critical part of cancer 
treatment for more than 70 years [29]. The 
cytotoxic drugs kill tumor cells and inhibit their 
proliferation through DNA damage, inhibiting 
DNA replication and arresting mitosis. However, 
cytotoxic chemotherapy is widely considered to 
be immunosuppressive because it can cause 
dose-dependent myelosuppression, suggesting 
antagonism with immunotherapy [30]. Before 
1994, to increase ACT immunotherapy and 
decrease side effects from chemotherapy for TIL 
to treat solid tumors, we began to study 
chemoimmunotherapy with techniques for 
primary tumor cells and immune cell separation 
and culture from the removed solid tumor tissues 
[31-33]. That time, to increase TIL efficacy and 
decrease toxic chemotherapy, we study 
chemoimmunotherapy through which the 
cultured TILs from solid tumors are activated and 
then infused into patients for Adoptive 
Immunotherapy. At the same time, the primary 
tumor cells from the tumor tissues are utilized as 
in vivo and in vitro chemosensitivity tests for 
chemoimmunotherapy [34-35], as shown in Fig.2. 
 
After more than thirty years effort, now 
chemoimmunotherapy combination regimens 
may have shown advantages over monotherapy: 
(1)  they can maximize cancer elimination within 
the range of tolerable toxicity; (2) target a wider 
range of tumor cells with different genetic and 

epigenetic abnormalities in a heterogeneous 
tumor population; (3) slow the development of 
drug resistance; (4) can shrink the primary tumor 
mass, reduce the number of ACT cells providing 
an opportunity for their combination with 
immunotherapy; (5) some chemotherapeutic 
agents may directly stimulate antitumor immunity 
with low infiltration of effector T cells within the 
tumor [36-38]. Now, we all know that the 
rationale in a chemoimmunotherapy combination 
can eliminate disseminated and metastatic 
cancer cells, although chemotherapy can cause 
myelosuppression. 
 

4. IMMUNE CHECKPOINT INHIBITING 
IMMUNE SUPPRESSION SUPPORTING 
IMMUNOTHERAPY 

 
Now, a suppression of tumor growth is emerging 
through target checkpoints as a new generation 
of antitumor therapy. There are two kinds of 
molecularly targeted checkpoint inhibitors. The 
first one is specifically killing tumors within the 
tumor microenvironment (TME), inhibiting the 
occurrence and development of tumors [39], and 
the second one can target and inhibit immune-
pathway molecules called the tumor immune 
microenvironment (TIME) [40] so that they can 
restore immune cell activity and improve the 
body's antitumor immune function. Currently, 
molecular target checkpoints increasingly studied 
within TIME are named Immune checkpoint 
inhibitors (ICIs) for PD-1, PD-L1, CTLA-4, TIM-3, 
LAG-3, and Siglec-15 by their corresponding 
molecular target inhibitors.  

 

 
 

Fig. 2. Clinical strategies for chemoimmunotherapy to increase TIL efficacy. 
NB. A clinical procedure combining TILs with sensitive chemotherapeutic agents, which were screened chemo-
sensitivity assay (CSA) from TIL cytotoxicity experiment of patient’s autogenous tumor cell to increase treatment 

response 



 
 
 
 

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Table 2. ICI combination 
 

Types Common ICI type supporting item  

ICI-ICI nivolumab ipilimumab 
ICI-ACT nivolumab Car-T/TIL 
ICI-chemotherapy nivolumab chemotherapy 
ICI antiangiogenic  nivolumab Antiangiogenic therapy 
ICI-vaccine nivolumab HPV16 specific peptide vaccine 
ICI-radiation nivolumab ionizing radiation 
ICI-TME nivolumab targeting TGFβ 
ICI-cytokine nivolumab IL2/IFN-gamma 

 
ICIs were initially approved for the treatment of 
melanoma. Due to single-agent ICIs' failure, 
combination regimens involving ICIs have been 
investigated, such as ICI-ACT, ICI-chemotherapy, 
and ICI antiangiogenic doublets, as shown in 
Table 2. Nivolumab and ipilimumab have shown 
initial success in melanoma and renal cell 
carcinoma (RCC). ICI-ICI combination therapy is 
a viable approach to overcome treatment 
resistance. Novel combination strategies to 
overcome ICI resistance rapidly evolve, with 
many clinical trials underway. Bispecific 
antibodies (bsAbs) allow the targeting of specific 
resistance mechanisms in a single molecule, and 
dual checkpoint inhibition of PD-L1 and LAG-3 is 
an example that has shown promising preclinical 
results. Other bsAbs combine ICIs with non-ICI 
immunotherapies, such as PD-L1 antibodies and 

transforming growth factor-β (TGF-β) traps, a key 
player in the development of an 
immunosuppressive tumor microenvironment 
(TME). Other forms of  ICI immunotherapy are 
also encouraging, including immunostimulatory 
cytokines (e.g., recombinant interleukin-2, 
interferon-α), cancer vaccines, and adoptive cell 
therapy. Combining vaccine therapies with ICIs 
may enhance antitumor effects in preclinical 
models. Combining CAR-T with ICIs may 
overcome some of the resistance mechanisms 
encountered. In addition, a combination of ICIs 
with ionizing radiation and ICIs with targeted 
therapies for cellular processes, including DNA 
damage repair, phosphatidylinositol 3-kinase, 
and histone deacetylase pathways. A logical 
approach to combination study design is needed 
to maximize patient benefit [41]. 

 

 
 

Fig. 3. Strategies for precision medicine for personalized T-cell therapy to increase T-cell 
efficacy 

NB. A) Improving TIL immune-response in experiment such as discover quiescent genes for TIL and neo-antigen 
from tumor cells; and rebuilding immune-response for TIL or set up Car-T or TCR-T cells; B) ICI improving T-cell 

to attack tumor cells; C) Targeting block to increase T-cell activity; D) TME block to increase T-cell activity; D) 
epigenetics treatment improving T-cell to attack tumor cells; and E) chemotherapy to increase T-cell attack tumor 

cells. 



 
 
 
 

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Fig. 4. Strategies for combination therapy to support immunotherapy 

 
5. A NEW GENERATION OF PRECISION 

MEDICINE SUPPORTING IMMUNO-
THERAPY  

 
According to those discussed above, distinct LD, 
chemotherapy, and ICI are different for individual 
patients. Of course, all combinations should differ 
from one person to another. Following thirty 
years of research, a new generation of precision 
medicine techniques is emerging [42-44].  
 

“To address the issues, successful precision 

medicine for tumor disease has involved immune 
cells/primary cell culture, tumor tissue biobanks, 
single cell technique, clinical genomics, and 
artificial intelligence in our laboratory” [45-50]. 
“Moreover, precision medicine is discovering 
driver genes, tumor proliferation, and tumor 
metastasis genes according to the updated 
strategy” [51]. Once we find distinct biomarkers 
in DNA level (SNP and epigenetics), RNA level 
microRNA, picoRNA, non-coding RNA), and 
protein level, we can develop precision medicine 
as Fig-3 to support immunotherapy. 
 

A. Specific personalized combination 
immunotherapy can be discovered 

 
“In the early period, we developed TIL culture for 
clinical applications by cultured TIL infusion in 
vivo for adoptive cell therapy (ACT) from solid 
tumors. After twenty-five efforts, we successfully 
developed our laboratory's single-cell techniques, 
clinical genomics, and artificial intelligence. After, 
we used single-cell genomics analysis to 
discover a set of upregulated quiescent genes 

such as Tob, LKLF, TGF-β, ERF, and 
REST/NRSF from the T-cells” [52-55]. “Moreover, 
after thirty years of effort, we know that TIL is a 
group of heterogeneous immune cells, so we can 
perform ex vivo heterogeneous TIL determining 
immune characteristics to kill autologous tumor 
cells and then treat the tumor patients based on 
immune characteristics for the tumor diseases 
[56]. Now we can measure quiescent status in 
the heterogeneous immune cells such as CD3+ 
T-cell (CD8+ T-cell and CD4+ T-cell), CD19+ B-
cell (tumor-infiltrating B-cells, TIL-B), 
CD16+/CD56+ NK cell (Natural killer Cell), 
CD16+/CD56+/CD3+ NKT cell (Natural Killer T-
cell), and other immune-cells (macrophage and 
neutrophil). Finally, the specific immune cells that 
have been specifically contacted to correspond 
with the tumor antigen of tumor cells will be 
cultured for precision immunotherapy. As we all 
know above, if we discover the higher expression 
of checkpoint-inhibiting molecules such as PD-1, 
which blocks immune cells, we can also further 
stimulate immune cells with PD-1 inhibitors to 
combine with the specific immune cells for 
personalized immunotherapy” [57-58].  
 

B. Molecular therapeutic targeting can be 
discovered 
 

Molecular targeted therapies are advanced 
therapeutic techniques that interfere with specific 
molecules to block cancer growth, progression, 
and metastasis [59-60]. Now, molecular targeted 
therapies approved by the Food and Drug 
Administration (FDA) have demonstrated 
remarkable clinical success in the treatment of a 



 
 
 
 

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253 

 

myriad of cancer types, including breast, 
leukemia, colorectal, lung, and ovarian cancers. 
We can also further develop immune cells with 
molecular targeted therapies to combine with 
specific immune cells to create personalized 
immunotherapy.  
 

C. TME targeting gene can be discovered 
 
“Tumor microenvironment (TME) and tumor cells 
in tumor tissue take many strategies to evade the 
host immune response by creating many 
immune-suppressive factors [61]. Thus, we can 
use the strategy from TME to be personalized 
therapy. TME consists of tissues, cells, and 
signaling molecules in tumor tissue, affecting the 
immune response to tumor cells. Furthermore, 
TME elements of tissues, cells, and molecule 
factors include those during the early period of 
tumor tissues and those in an aggressive period 
in tumor tissues. Identifying and regulating TME 
cells and regulating molecules such as 
extracellular matrix (ECM) and pathways such as 
adenosine (ADO) and indole-2,3-dioxygenase 
(IDO) may guide a new generation of precision 
medicine so that we can use TME targeting 
components to combine with the specific   
immune cells to personalized immunotherapy”  
[5]. 
 

D. Epigenetics targeting can be 
discovered 

 
Epigenetic therapy is based on methylation 
assay and PTM histone assay [62-65]. 
Methylated cytosines recruit protein complexes 
that promote functionally inactive 
heterochromatin under a global decrease in DNA 
methylation, such as 5-azacitidine (AZA) and 
decitabine (DEC), by inhibiting DNMT1. 
Epigenetic therapy based on PTM histone assay 
is HDAC inhabitation, which removes the acetyl 
groups from the lysine residues to apply for an 
option for tumor treatment so that we can use 
epigenetic therapy to combine with the                
specific immune cells for personalized 
immunotherapy. 
 

E. Specific chemotherapy can be 
discovered 

 
Customized chemotherapy has now been 
applied to the field of cancer [66-70]. According 
to genomic data, we can also use personalized 
chemotherapy to develop immunotherapy with 
specific immune cells and specific chemotherapy 
for personalized immunotherapy. 

6. CONCLUSION  
 
The "foe" or "friend" of chemotherapy combined 
with immunotherapy is a long-term puzzling issue. 
Cytotoxic chemotherapy is considered to be 
immunosuppressive while it is recommended  to 
support immunotherapy in clinical application, to 
increase ACT immunotherapy, and to reduce the 
side effects of chemotherapy, we have 
experienced several decades to study the 
mechanism using isolating and culturing primary 
tumor cells and immune cells from patient 
specimens such as resected solid tumor tissues. 
After about 30-40 years of effort, the optimizing 
combination has proved that chemotherapy 
combined with immunotherapy is superior to 
monotherapy. Based on our current publications, 
including other clinical laboratory work, the 
manual introduced four areas of combination 
therapy: lymphodepletion (LD), 
chemoimmunotherapy (CI), ICI combined with 
immunotherapy, and precision medicine (PM) 
supporting Immunotherapy as Fig. 4. Precision 
medicine based on patients’ information includes 
patient specimen biobanks, single-cell 
technologies, clinical genomics, and artificial 
intelligence to support combination therapy. 
Based on 30-40 years of R&D to improve patient 
immunotherapy, now is an excellent time to 
define combination therapy and evaluate its 
efficacy in oncological diseases.  
 

DISCLAIMER (ARTIFICIAL INTELLIGENCE) 
 
Author(s) hereby declares that NO generative AI 
technologies such as Large Language Models 
(ChatGPT, COPILOT, etc) and text-to-image 
generators have been used during writing or 
editing of this manuscript.  
 
 

Details of the Machine-learning (AI) usage is 
given below: 
 

1. Cytoscape platform integrated by topology 
algorithm. 
2.  Galaxy Server for next generation sequencing 
analysis. 
3. Gene Chip expression console for microarray 
data for gene expression and BRB Array tool for 
gene expression signature (GES). 
 

ACKNOWLEDGMENTS 
 
Under the support of Dr. H. D. Preisler, we have 
set up a method to analyze genomic profiles from 
tumor cells and TIL. This work was supported by 



 
 
 
 

Li and Li; Asian J. Immunol., vol. 7, no. 1, pp. 247-257, 2024; Article no.AJI.126682 
 
 

 
254 

 

the National Cancer Institute IRG-91-022-09, 
USA (to BL). Mentions of trade names or 
commercial products in this article are solely for 
the purpose of providing specific information and 
do not imply recommendation. 
 

CONSENT 
 
It is not applicable. 
 

ETHICAL APPROVAL 
 
It is not applicable. 

 
COMPETING INTERESTS 
 
Authors have declared that no competing 
interests exist. 
 

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