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CAR-T CELL THERAPY SURVIVORSHIP

Sassine Ghanem MD

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BACK TO THE BASICS

Source: Fesnak, A., June, C. & Levine, B. Engineered T cells: the promise and challenges of cancer immunotherapy. Nat Rev Cancer 16, 566–581 (2016)

Endogenous TCRs recognize intracellularly processed antigens that must be presented in the context of the major histocompatibility complex (MHC) and require co-stimulatory signals for complete T cell activation.

T cell receptors (TCRs) provide a recognition signal (Signal 1) for T cells complemented by a co-stimulatory signal that can provide an on/off signal to regulate the activation of T cells (Signal 2).

A TCR may recognize either intracellular or extracellular antigen in the context of major histocompatibility complex (MHC) presentation. When designing a TCR to target tumour cells, having the option to target intracellular tumour antigen may be advantageous as this may expand the pool of potential targets. Conversely, many tumors downregulate MHC class I expression, potentially masking their presence from a TCR-engineered T cell.

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DEVELOPMENT OF CARS

Source: Fesnak, A., June, C. & Levine, B. Engineered T cells: the promise and challenges of cancer immunotherapy. Nat Rev Cancer 16, 566–581 (2016)

CARs enable highly specific targeting of antigen in an MHC-independent fashion. CARs are formed from a combination of antibody-derived or ligand derived domains and TCR domains. A CAR is commonly composed of a specificity-conferring, B cell receptor (BCR)-derived, extracellular antibody single-chain variable fragment (scFv), a TCR-derived CD3 domain and one or more intracellular co-stimulatory domains. Until recently, CAR T cell targets were limited to extracellular tumour antigens.

Chimeric antigen receptors (CARs), on the other hand, lack TCR α and β chains. The extracellular portion of a CAR consists of single-chain variable fragments derived from immunoglobulin heavy chain variable (VH) and Ig light chain variable (VL) domains. Typically these are then fused to a transmembrane domain, an intracellular co-stimulatory domain and an intracellular CD3ζ chain domain. Again, CARs must recruit endogenous downstream signalling molecules to transduce activating signal, but co-stimulation is provided in cis and in response to the same activating signal. CARs recognize cell surface antigens independently of the MHC and are therefore not tissue type restricted. ICOS, inducible T cell co-stimulator.

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EVOLUTION OF CAR T

Source: Fesnak, A., June, C. & Levine, B. Engineered T cells: the promise and challenges of cancer immunotherapy. Nat Rev Cancer 16, 566–581 (2016)

Chimeric antigen receptor design and evolution. Chimeric antigen receptors (CARs) target surface antigens in a major histocompatibility complex (MHC)-independent manner and consist of an extracellular binding domain, hinge domain, transmembrane domain and intracellular signalling domains. The first clinical trials tested CARs that had a binding domain composed of native CD4 that bound to the envelope glycoprotein gp120 expressed by HIV-infected cells188,189, with a single T cell receptor (TCR) signalling domain composed of the CD3ζ chain190–192. CARs with an extracellular domain composed of antibody single-chain variable fragments (scFvs) were first reported by Kuwana193 and later by Eshhar and colleagues194,195. Second-generation CARs incorporating CD28 as a co-stimulatory domain were first developed by Roberts (US Patent 5,686,281) and reported by Finney196, and those incorporating 4‑1BB as a co-stimulatory domain were developed and reported by Finney197,198, Imai199 and then others200,201. CARs incorporating three or four signalling domains, so called ‘third-and fourth-generation’ CARs, have also been developed and are beginning to be tested in clinical trials83,202,203. VH, immunoglobulin heavy chain variable domain; VL, immunoglobulin light chain variable domain.

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CD19

Mostolizadeh. Numer Algebra Control Optim. 2018;8:63. Wang. Exp Hematol Oncol. 2012;1:36.

Y

Pre B-ALL

B-cell lymphomas and leukemias

Myelomas

Stem cell

Pre B

Immature B

Mature B

Plasma cell

Pro B

CD19

CD22

CD20

Y

BCMA

Immunoglobulin

BM

LN

BM, LN

Pro-B

Pre-B

Transitional

Naive

GC-B

Memory

Plasmablast

PC

Short-lived PC

Long-lived PC

MM

BCMA

BAFF-R

Source: Cho. Front Immunol. 2018;9:1821. Moreaux. Blood. 2004;103:3148. Sanchez. Br J Haematol. 2012;158:727.

Prototypical target antigen CD-19

CD19 expression is restricted to B-cells and possibly follicular dendritic cells

CD19 is not expressed on pluripotent bone marrow stem cells

CD19 is expressed on the surface of most B-cell malignancies

Antibodies against CD19 inhibit growth of tumor cells

But also to launch the field of CAR T – Common malignancies B cell – no issues with tissue trafficking to the tumor microenvironment - B cell aplasia is a manageable toxicity where we have some experience in managing and it is relatively less fatal

Upon terminal differentiation, plasma cells downregulate many common engineered T cell targets such as CD19, CD20, CD22 and surface Ig light chains. Therefore, to effectively target malignant plasma cells in conditions such as multiple myeloma, new targets must be considered. One such target, B cell maturation antigen is analogous to CD19 in that it is expressed in most cases of multiple myeloma and is not expressed on non-plasma cells. Unlike CD19, however, BCMA signalling can induce plasma cell proliferation and survival. Therefore, downregulation of BCMA by multiple myeloma cells to escape engineered T cell detection could limit tumour progression.

BCMA: antigen expressed specifically on PCs and myeloma cells

Cell-surface receptor in TNF superfamily

Higher expression on myeloma cells than normal PCs

Not expressed in other tissues

Key role in B-cell maturation and differentiation

Promotes myeloma cell growth, chemotherapy resistance, immunosuppression in bone marrow microenvironment

Expression of BCMA increases with progression from MGUS to advanced myeloma

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NON CD-19 TARGET ANTIGENS

Source: Grover et al Extending the Promise of Chimeric Antigen Receptor T-Cell Therapy Beyond Targeting CD19+ Tumors. J Clin Oncol. 2021 Feb 10;39(5):499-513.

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Source: Morgan RA, et al. Mol Ther. 2010 Apr;18(4):843-51.

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CAR T PROCESS

Source: Fesnak, A., June, C. & Levine, B. Engineered T cells: the promise and challenges of cancer immunotherapy. Nat Rev Cancer 16, 566–581 (2016)

We now have the structure, we now have the target antigen, how to do we introduce this into the tumor microenvironment?

Engineered T cell manufacturing. Leukocytes are generally collected by leukapheresis (step 1) and lymphocytes can be enriched (step 2) by counterflow centrifugal elutriation204 or subsets selected according to cellular phenotype (not shown). The enriched lymphocytes are placed in culture and (step 3) stimulated with bead-based artificial antigen presenting cells and viral vector (step 4) is added. The culture is expanded in a bioreactor for several days (step 5) and then the T cell bulk product (step 6) is washed and concentrated, samples are removed for quality control release testing (step 7) and quality assurance review. The final formulation is cryopreserved (step 8), enabling easy shipment to distant infusion sites, where the final product bag (step 9) is thawed and infused. Manufacturing time is generally 5–10 days, and collection to infusion times can range from 2 to 4 weeks depending on patient clinical status and chemotherapy conditioning regimens.

Would the patient be able to go through leukapheresis (without immediate use of steroids/chemotherapy) and remain stable until the T-cell infusion (3-4 wks)?
Does the patient need alternative therapy prior to CAR T-cell therapy consideration?

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COMMERCIAL CD19 CAR T PRODUCTS

	Axicabtagene Ciloleucel^[1]	Tisagenlecleucel^[2]	Lisocabtagene Maraleucel^[3]	Brexucabtagene Autoleucel^[4]
Construct	Anti–CD19-CD28-CD3z	Anti–CD19-41BB-CD3z	Anti–CD19-41BB-CD3z	Anti–CD19-CD28-CD3z
Dose	2 x 10⁶/kg (max 2 x 10⁸)	0.6 to 6.0 x 10⁸/kg	50 to 150 x 10⁶	2 x 10⁶/kg (max 2 x 10⁸)
Lymphodepletion	Flu/Cy 30/500 x 3 days	Flu/Cy 25/250 x 3 days, or bendamustine x �2 days	Flu/Cy 30/300 x 3 days	Flu/Cy 30/500 x 3 days

Source: 1. Neelapu. NEJM. 2017;377:2531. 2. Maude. NEJM. 2018;378:439. 3. Abramson. ASH 2019. Abstr 241. 4. Wang. NEJM. 2020;382:1331.

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A JOURNEY DOWN THE PATH OF CAR T

Source: Tallantyre, E.C et al. Neurological updates: neurological complications of CAR-T therapy. J Neurol 268, 1544–1554 (2021).

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PRE-INFUSION

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INFECTIOUS COMPLICATIONS

Source: Hill JA, Seo SK. How I prevent infections in patients receiving CD19-targeted CAR-T cells for B-cell malignancies. Blood. 2020 Aug 20;136(8):925-935.

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INFECTIOUS PROPHYLAXIS

Source: Hill JA, Seo SK. How I prevent infections in patients receiving CD19-targeted CAR-T cells for B-cell malignancies. Blood. 2020 Aug 20;136(8):925-935.

Levofloxacin only when neutropenic or if outpatient center dependent or after chemotherapy (MSK practice).

The use of granulocyte colony-stimulating factors (G-CSF) may be considered after CAR-T cell infusion in patients with an ANC <500 (At MSK not before Day 21 with resolution of CRS and neurotoxicity) the reason for that is a theoretical risk of increasing risk for or exacerbating CRS or ICANS.

Acyclovir or Valacyclovir for at least 6 months or longer if CD4 less than 400.

Antifungal prophylaxis during period of neutropenia (especially for ALL patients, in DLBCL certain centers use high risk criteria: - High risk or prior invasive fungal infection - Prolonged neutropenia (>3 weeks) - On systemic steroids >0.5 mg/kg/day (prednisone equivalent)).

PCP prophylaxis commence with chemotherapy (as per MSKCC) and continue for 6 months post-CAR T infusion.

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NEUROLOGICAL PROPHYLAXIS

Source: Yanez L, Sanchez-Escamilla M, Perales MA. CAR T Cell Toxicity: Current Management and Future Directions. HemaSphere, 2019;3:2.

Although the pathogenesis of neurotoxicity is not fully understood and was first thought to be related to direct parenchymal CAR T cells toxicity, recent studies suggest that the dysfunction of the blood brain barrier (BBB) is the main factor. The BBB is formed by capillary endothelial cells surrounded by extracellular matrix (basal lamina), pericytes, microglia and astrocytes. In addition to other factors, impairment of the BBB function has been related to TNF-a, IL-6, IL-1 and the angiotensin 1 (ANG1) and angiotensin 2 (ANG2) balance. All these factors, as well as other molecules implicated in the expansion and activation of the CART cells, myeloid cells, monocyte and macrophages (IFN-g, IL-10, G-CSF, GM-CSF, IL-8, MCP-1), and neurotoxic substances such as glutamate and quinolinic acid, have been found to be elevated in severe forms of CAR T cells neuro toxicity.

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PERI- INFUSION DAYS 0-28

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ASTCT CONSENSUS CRITERIA

Source: Lee et al. ASTCT Consensus Grading for CRS and ICANS. Biol Blood Marrow Transplant. 2019 Apr;25(4):625-638.

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CYTOKINE KINETICS

Source: Hay et al. Kinetics and biomarkers of severe cytokine release syndrome after CD19 CAR T-cell therapy. Blood. 2017 Nov 23;130(21):2295-2306.

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TIME COURSE OF TOXICITIES ASSOCIATED WITH �FDA-APPROVED CAR T-CELL THERAPIES

Number of Days (Range)	CRS		Neurologic AEs
Number of Days (Range)	Median Time �to Onset	Median �Duration	Median Time �to Onset	Median Duration
Axicabtagene ciloleucel¹	2 (1-12)	7 (2-58)	4 (1-43)	17
Brexucabtagene autoleucel²	3 (1-13)	10 (1-50)	6 (1-32)	2 (2-454)
Tisagenlecleucel³	3 (1-51)	8 (1-36)	6 (1-359)	ALL: 6�DLBCL: 14
Idecabtagene Vicleucel⁴	1 (1-12)	5 (1-63)	2 (1-10)	3 (1-26)

Source: 1. Neelapu. NEJM. 2017;377:2531. 2. Wang. NEJM. 2020;382:1331. 3. Schuster. NEJM. 2019;380:45. 4. Munshi N Engl J Med 2021; 384:705-716

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ASTCT CONSENSUS: ICE EXAM

Orientation: orientation to year, month, city, hospital: 4 points
Naming: ability to name 3 objects (eg, point to clock, pen, button): 3 points
Following commands: ability to follow simple commands (eg, “Show me 2 fingers” or “Close your eyes and stick out your tongue”): 1 point
Writing: ability to write a standard sentence (eg, “Our national bird is the bald eagle”): 1 point
Attention: ability to count backwards from 100 by 10: 1 point

Source: Lee et al. ASTCT Consensus Grading for CRS and ICANS. Biol Blood Marrow Transplant. 2019 Apr;25(4):625-638.

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ASTCT CONSENSUS CRITERIA

Source: Lee et al. ASTCT Consensus Grading for CRS and ICANS. Biol Blood Marrow Transplant. 2019 Apr;25(4):625-638.

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Source: Yáñez L, Alarcón A, Sánchez-Escamilla M, et al. How I treat adverse effects of CAR-T cell therapy. ESMO Open 2020;4:e000746.

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TOXICITY MANAGEMENT BY GRADE

Grade	CRS	Neurotoxicity	CRS + Neurotoxicity
1	Supportive care	Supportive care	Supportive care
2	Tocilizumab	Steroids (dexamethasone or methylprednisolone)	Tocilizumab + steroids (dexamethasone)
3	Tocilizumab	Steroids (dexamethasone)	Tocilizumab + steroids (dexamethasone)
4	Tocilizumab + high-dose steroids�ICU/critical care	High-dose steroids (methylprednisolone)�ICU/critical care	Tocilizumab + high-dose steroids (methylprednisolone) �ICU/critical care

Source: Lee et al. ASTCT Consensus Grading for CRS and ICANS. Biol Blood Marrow Transplant. 2019 Apr;25(4):625-638.

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Class Effects of the Cell-Mediated Immune Response: �CRS and Neurotoxicity

Source: 1. Maude. NEJM. 2018;378:439. 2. Shah. ASCO 2019. Abstr 7006. 3. Schuster. NEJM. 2019;380:45. 4. Neelapu. NEJM. 2017;377:2531. 5. Abramson. ASH 2019. Abstr 241. 6. Wang. NEJM. 2020;382:1331. 7. Munshi N Engl J Med 2021; 384:705-716

	B-ALL		DLBCL			MCL	MM
	ELIANA^[1]	ZUMA-3^[2]	JULIET^[3]	ZUMA-1^[4]	TRANSCEND^[5]	ZUMA-2^[6]	KARMMA^[7]
CAR T-cell agent	Tisagenlecleucel	Brex. autoleucel	Tisagenlecleucel	Axicabtagene ciloleucel	Lisocabtagene maraleucel	Brex. autoleucel	Idecabtagene Vicleucel
N treated	75	45	111	101	269	68	128
CRS, %	77*	93^†	58*	93^†	42^†	91^†	84^†
Grade ≥ 3 CRS, %	46*	29^†	22*	13^†	2^†	15^†	5^†
NT, %	40	78	21	64	30	63	18
Grade ≥ 3 NT, %	13	38	12	28	10	31	3

*Per Penn scale. ^†Per Lee Scale.

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MAJOR CRS CRITERIA

Source: Schuster et al. Grading and management of CRS in patients treated with tisagenlecleucel in the JULIET trial. Blood Advances, 4(7), 1432-1439.

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VARIATION BETWEEN CRS CRITERIA

Source: Schuster et al. Grading and management of CRS in patients treated with tisagenlecleucel in the JULIET trial. Blood Advances, 4(7), 1432-1439.

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COAGULOPATHY AND CRS

Source: Shao et al. CRS-related coagulopathy in BCMA targeted CAR-T therapy: a retrospective analysis in a phase I/II clinical trial. Bone Marrow Transplant (2021).

Tissue factor and monocyte connect the network of coagulation and CRS. Tissue factor binds to protease-activated receptors, then exhibit inflammatory signals including the production of cytokines like TNF-α, IL-6. Monocyte is the key cell component to produce CRS-related cytokines like IL-6, IL-1, and NO, which could up-regulate TF expression, leading to TF-related coagulopathy. FXII could autoactivates to generate FXIIa, which recruits high molecular weight kininogen complexed with prekallikrein. Kallikrein was then activated and envokes HK to release bradykinin (BK). BK could trigger pro-inflammatory responses by binding to receptors, like kinin B1/B2 receptors, on endothelial cells and neutrophils. Upon activation, platelets release α-granules like soluble P-selectin to act on monocyte receptors to upregulate pro-inflammatory functions.

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COAGULOPATHY AND CRS

Source: Shao et al. CRS-related coagulopathy in BCMA targeted CAR-T therapy: a retrospective analysis in a phase I/II clinical trial. Bone Marrow Transplant (2021).

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COAGULOPATHY

Source: Buechner et al. Practical guidelines for monitoring and management of coagulopathy following tisa-cel CAR T-cell therapy. Blood Adv. 2021 Jan 26;5(2):593-601.

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POST - INFUSION DAYS 29- X

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PHASES OF OPPORTUNISTIC INFECTIONS

Source: Hill JA, Seo SK. How I prevent infections in patients receiving CD19-targeted CAR-T cells for B-cell malignancies. Blood. 2020 Aug 20;136(8):925-935.

When do patients recover neutrophils, CD4-positive T cells, and CD19-positive B cells after CD19-targeted CAR-T cell therapy? The lymphodepleting chemotherapies most commonly used prior to CAR T-cell infusion, cyclophosphamide and fludarabine, contribute to cytopenias that may persist for months with associated risks for opportunistic infections.6,7 Cytopenias persisting >90 days after CD19-targeted CAR-T cell therapy have been reported in 16% of patients with ongoing remission.8 The majority of patients develop severe neutropenia for a median of 7-10 days.9–11 One study reported absolute CD4-positive T cell counts >200 cells/mm3 in only 63% of patients by 1 year after treatment with axicabtagene ciloleucel for R/R large B cell lymphomas. Almost all patients who respond to CD19 CAR-T cell therapy develop CD19-positive B cell aplasia within the first 28 days, which can persist for >1 year due to on-target, off-tumor side-effects (Figure 1).12–14 However, polyclonal CD19-positive B cells can recover in patients with sustained remission and has been described in up to 50% of pediatric and adult patients by 6-12 months after CAR-T cell infusion.

Pivotal trials using tisagenlecleucel and axicabtagene ciloleucel report any infection in up to 55% of patients within the first 1 to 2 years, and infections of at least grade 3 severity in up to 33% of patients.1-6 Fatal infections are rare and reported in ,5% of treated patients. In 3 studies focusing on infections after CD19-CAR–T-cell therapy using noncommercial products in children and/or adults with ALL, non- Hodgkin lymphoma, and/or chronic lymphocytic leukemia, the cumulative incidence of any microbiologically documented infection within the first month was as high as 40%.7,50,51 Most infections were bacterial, and almost all instances of bacteremia occurred within the first 2 weeks after CAR–T-cell infusion. Respiratory viral infections were the next most frequent. Cases of HSV and VZV reactivation in patients not adhering to acyclovir prophylaxis have been reported, but infections with other herpesviruses and double-stranded DNA viruses (eg, adenovirus, BK polyomavirus) appear to be infrequent. Invasive fungal infections occur in up to 8% of patients, including mold infections.

Infection rates after the first month were less frequent and usually due to respiratory viruses.

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CYTOPENIAS - NEUTROPENIA

Source: Munshi et al Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma. N Engl J Med. 2021 Feb 25;384(8):705-716.

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CYTOPENIAS - THROMBOCYTOPENIA

Source: Munshi et al Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma. N Engl J Med. 2021 Feb 25;384(8):705-716.

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PROLONGED CYTOPENIAS

Etiology:

Initial: Lymphodepleting chemotherapy
Late: unclear; possible immune-related secondary to CAR T-cells
Bone marrow biopsy in most cases shows hypocellularity

Incidence:

ZUMA-1

17% of 108 patients had grade 3 cytopenias beyond 3 months (11% neutropenia, 7% thrombocytopenia, 3% anemia)

27 months only 2% had grade 3 cytopenias

JULIET

24% of patients had > grade 3 neutropenia and 41% of patients had > grade 3 thrombocytopenia at day +28

38% had unresolved thrombocytopenia at month 3

Locke et al., 2019; Schuster et al., 2019

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HYPOGAMMAGLOBULINEMIA

Source: Hill JA, Seo SK. How I prevent infections in patients receiving CD19-targeted CAR-T cells for B-cell malignancies. Blood. 2020 Aug 20;136(8):925-935.

Based on purely extrapolated data

Hypogammoglobulinemia, often requiring immunoglobulin G (IgG) replacement, occurred in 41% of patients 90 days after CAR T-cell infusion in one study cohort (Cordeiro et al., 2018).

IgG levels typically fall 1 to 3months after CART infusion and can remain low up to 4 years, but some patients can maintain antibody-secreting memory plasma cells contributing to long lasting humoral immunity.

There are differences in the management of hypogammaglobulinemia between children and adults. While replacement is typically done in pediatric patients, adult centers reserve the administration of intravenous immunoglobulin (IVIG) in those patients with severe or recurrent infections. The recommended dose of IVIG replacement for primary immunodeficiency is 400 to 600mg/kg every 3 to 4 weeks. Replacement treatment with IVIG should be maintained until IgG levels ≥ 400mg/dl.

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VACCINATION

6 months for Killed/Inactivated vaccines
One year for Live vaccines

Source: Hill JA, Seo SK. How I prevent infections in patients receiving CD19-targeted CAR-T cells for B-cell malignancies. Blood. 2020 Aug 20;136(8):925-935.

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VACCINATION

Response: At least twofold increase in IgG from prevaccination to 1 to 2 months postvaccination or achieving a seroprotective IgG level at 1 to 2 months postvaccination

Source: Hill JA, Seo SK. How I prevent infections in patients receiving CD19-targeted CAR-T cells for B-cell malignancies. Blood. 2020 Aug 20;136(8):925-935.

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Source: Hill JA, Seo SK. How I prevent infections in patients receiving CD19-targeted CAR-T cells for B-cell malignancies. Blood. 2020 Aug 20;136(8):925-935.

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WHEN TO ASSESS FOR RESPONSE?

Tisagenlecleucel – B-ALL¹

Bone Marrow Biopsy and aspirate with MRD testing at Day + 28 then clinically as needed

Tisagenlecleucel – DLBCL²

CT at Day 28 and Months 6, 9, 12, 18, 24, 36, 48 and 60 and as indicated
PET/CT at month 3

Axicabtagene ciloleucel - DLBCL³

First post–axi-cel PET-CT at 4 weeks after infusion, at month 3 and every 3 months thereafter up to 2 years post–axi-cel infusion.
After 2 years, PET-CT scans were performed as clinically indicated and/or per the institution’s standard of care.

Source: 1. Maude. NEJM. 2018;378:439. 2. Schuster. NEJM. 2019;380:45. 3. Neelapu. NEJM. 2017;377:2531.

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WHEN TO ASSESS FOR RESPONSE?

Brexucabtagene autoleucel – Mantle Cell Lymphoma¹

PET/CT at 4 weeks after infusion and then regularly thereafter

Idecabtagene cileucel – Multiple Myeloma²

Monthly SPEP/IFE, UPEP/IFE, Serum Free light chains and Quantitative serum Ig
PET/CT at Months 1, 3, 6, 12, 18 and 24
Bone Marrow Biopsy and Aspirate with MRD assessment at Months 1, 3, 6, 12, 18 and 24

Source: 1. Wang. NEJM. 2020;382:1331. 2. Munshi N Engl J Med 2021; 384:705-716

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SECONDARY MALIGNANCIES

Report of 15% of 86 adult CLL/NHL patients developed secondary malignancies

Non-melanoma skin cancer: 7%
Myelodysplastic syndrome: 5%
Melanoma: 1%
Non-invasive bladder cancer: 1%
Multiple myeloma: 1%

Median number of previous lines of therapy: 4

62% previous autologous/allogeneic stem cell transplant

Cordeiro et al 2020

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SECONDARY MALIGNANCIES

The incidence of new cancers is generally low after CAR-T cell therapy and appears to be largely driven by other risk factors including previous chemotherapy and/or radiation.
Ongoing vigilance is nevertheless required for the small potential risk of secondary malignancy arising from insertional oncogenesis.
Long-term survivors should have age-appropriate cancer screening performed along with periodic monitoring of blood counts to screen for therapy-related myeloid neoplasms, which have been reported in 5%–10% of patients.

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LATE IMMUNE EFFECTS

Late immune related events were seen in 8% of 86 patients at a median of 234 days after cell infusion

Lymphocytic alveolitis
Persistent skin rash
Eosinophilic pneumonia
Pneumonitis
Collagenous colitis
Granulomatous disease

Cordeiro et al 2020

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LATE IMMUNE EFFECTS

20% of patients who received CAR T-cells after an allogenic stem cell transplant developed GVHD 2-3 months post cell infusion.
Management: lack of consensus guidelines; often treated with corticosteroids

Cordeiro et al 2020

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OTHER LONG-TERM SEQUELAE

Fertility preservation
Fatigue
Neuropsychiatric disturbances
Psychosocial Disturbances

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FERTILITY PRESERVATION

Successful pregnancies have been reported in small numbers of CAR-T cell recipients.
Fertility preservation options should be discussed prior to CAR-T cell therapy for patients with child-bearing potential.
The optimal time to conceive a child is not yet known, but effective contraception is recommended for >6–12 months after fludarabine and cyclophosphamide-based lymphodepleting chemotherapy.
Further research is needed into the reproductive considerations of CAR-T cell therapy and the impact on a developing fetus.

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CARTITUDE-1: Neurotoxicity (NT)

All patients with ICANS recovered
Other NTs resolved in 6 patients, and did not resolve in 6 patients:

1 patient has ongoing NT
1 patient died from NT complications
4 patients died of other causes

No other movement and neurocognitive AEs observed in the CARTITUDE development program

Neurotoxicities, n (%)	All Patients (N = 97)
Neurotoxicities, n (%)	All Grade	Grade ≥ 3
Total CAR T-cell NT AEs	20 (20.6)	10 (10.3)
ICANS	16 (16.5)	2 (2.1)
Other NTs*	12 (12.4)	9 (9.3)

Characteristic	ICANS	Other NT*
Median time to onset, days (range)	8 (3-12)	27 (11-108)
Median time to recovery, days (range)	4 (1-12)	75 (2-160)

*Other neurotoxicities occurred after CRS and/or ICANS resolved; included

5 patients with movement and/or neurocognitive changes, 7 patients with

nerve palsy, peripheral motor neuropathy.

Madduri. ASH 2020. Abstr 177.

Slide credit: clinicaloptions.com

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a, FDG-PET/CT shows decreased uptake in the caudate nucleus after development of neurotoxicity (POST, right, day 134 after CAR-T infusion), compared to previous imaging before development of neurotoxicity symptoms (PRE, left, day 77 after CAR-T infusion). Prior FDG-PET/CT imaging (before CAR-T infusion) was similar to the pre-neurotoxicity scan. The scatter plot on the right illustrates the normalized z-score of different regions of the brain before and after CAR-T infusion. The caudate is highlighted. The normalized score is calculated using MIMneuro, comparing the image with a library of 43 FDG neurologic controls (41–80 years old). b, Visual representation of the expression of DRD1 and TNFRSF17 (BCMA) in a single patient from the Allen Brain Atlas. Expression of both genes (left, red = high) overlaps with the caudate nucleus region shown in three dimensions (right, purple). Image credit: Allen Institute for Brain Science (2010). c, H&E staining of the caudate nucleus subependymal region (×10 magnification; scale bar, 200 µm). d, GFAP immunohistochemistry of the caudate nucleus subependymal region (×10 magnification; scale bar, 200 µm). e, CD3 immunohistochemistry of the caudate nucleus subependymal region (×10 magnification; scale bar, 200 µm). f, BCMA immunohistochemistry of the caudate nucleus subependymal region (×10 magnification; scale bar, 200 µm; inset, ×40 magnification showing a neuron staining positively). c–f, Images shown are representative slides from the caudate nucleus from the patient described in this case report (n = 1). For each stain, at least three slides were available showing similar results.

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a, FDG-PET/CT shows decreased uptake in the caudate nucleus after development of neurotoxicity (POST, right, day 134 after CAR-T infusion), compared to previous imaging before development of neurotoxicity symptoms (PRE, left, day 77 after CAR-T infusion). Prior FDG-PET/CT imaging (before CAR-T infusion) was similar to the pre-neurotoxicity scan. The scatter plot on the right illustrates the normalized z-score of different regions of the brain before and after CAR-T infusion. The caudate is highlighted. The normalized score is calculated using MIMneuro, comparing the image with a library of 43 FDG neurologic controls (41–80 years old). b, Visual representation of the expression of DRD1 and TNFRSF17 (BCMA) in a single patient from the Allen Brain Atlas. Expression of both genes (left, red = high) overlaps with the caudate nucleus region shown in three dimensions (right, purple). Image credit: Allen Institute for Brain Science (2010). c, H&E staining of the caudate nucleus subependymal region (×10 magnification; scale bar, 200 µm). d, GFAP immunohistochemistry of the caudate nucleus subependymal region (×10 magnification; scale bar, 200 µm). e, CD3 immunohistochemistry of the caudate nucleus subependymal region (×10 magnification; scale bar, 200 µm). f, BCMA immunohistochemistry of the caudate nucleus subependymal region (×10 magnification; scale bar, 200 µm; inset, ×40 magnification showing a neuron staining positively). c–f, Images shown are representative slides from the caudate nucleus from the patient described in this case report (n = 1). For each stain, at least three slides were available showing similar results.

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HEALTH LITERACY IN VULNERABLE POPULATIONS

“They did not tell me”

A 42-year-old Latina who had 20 years of experience as an RN noted, I got a big fat booklet at the very beginning, but I didn’t think it gave me much information of what to expect. Like, just about two days before I came in, I found out that I have to be on a no-fresh-fruits, no-vegetables [diet], even throughout the three months that I am going to be out. . . . I had to learn [that] by eavesdropping.

“Decision Dilemmas”

A 39-year-old African American man who worked as an auto mechanic illustrated his dilemma with refusal. He said, “It was a situation where the only say-so I could have was just to refuse, but, by that time, they had so scared me at that point, I am like, ‘okay.’”

“Fears of dying”

A 63-year-old Latino who worked as an agricultural worker expressed his fear of death when he said, “You are scared of dying before your time, and that the transplant might not work and I would die during the procedure.”

Source: Cohen MZ et al. Understanding health literacy in patients receiving hematopoietic stem cell transplantation. Oncol Nurs Forum. 2013 Sep;40(5):508-15.

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HEALTH LITERACY IN VULNERABLE POPULATIONS

Tough Symptoms and Side effects

A 57-year-old Caucasian woman who worked as an RN explained: The mouth sores. . . . [you] hear about them peripherally.. . . When they came, I started sucking on popsicles and ice, and I thought, “What is going on here?” So a little more education on my part would have been better.

Relying on others

A 64-year-old Latino who worked as a crane operator stated, I just know what the doctor told me. My wife went on the Internet and found all of this different stuff out, and she passed it on to me. I didn’t do it. She did it for me, and that is how I got my information. . . She does a lot for me.

Source: Cohen MZ et al. Understanding health literacy in patients receiving hematopoietic stem cell transplantation. Oncol Nurs Forum. 2013 Sep;40(5):508-15.

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SPECIFICALLY FOR NEW OR EXPERIMENTAL TREATMENTS

Guinea Pig

“…I don’t wanna be a guinea pig either. I don’t want you to give me something and then say, well this might, you know, I don’t know how it’s gonna affect you, this might do this, I can’t really say, you know doctors always say that.”

IRB protection

“I don’t think it [knowing of IRB protections] would make people likely to participate because I think on average people from the African American and Hispanic community are distrustful of government. And just because you tell them that they’re being protected by this agency, that they probably have never heard of before, and have no idea that it even may exist, they’re probably not going to believe you.”

Source: Evans, K. R., Lewis, M. J., & Hudson, S. V. (2011). The Role of Health Literacy on African American and Hispanic/Latino Perspectives on Cancer Clinical Trials. Journal of Cancer Education, 27(2), 299–305.

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Cost

Adherence

Respect of patient’s values

Clinical Benefit

Health Literacy

Scheduling

and administration

Social Support

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WHAT ABOUT COSTS?

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Source: Lee SJ et al. Anti B-Cell Maturation Antigen CAR T-cell and Antibody Drug Conjugate Therapy for Heavily Pre-Treated Relapsed and Refractory Multiple Myeloma; Evidence Report. Institute for Clinical and Economic Review, April 5, 2021.

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Source: Lee SJ et al. Anti B-Cell Maturation Antigen CAR T-cell and Antibody Drug Conjugate Therapy for Heavily Pre-Treated Relapsed and Refractory Multiple Myeloma; Evidence Report. Institute for Clinical and Economic Review, April 5, 2021.

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MULTIDISCIPLINARY TRAINING

Essential Steps and Required Personnel for a CAR T-Cell Program

INTAKE

Non-CAR MDs
Administrative staff
Financial coordinator

CONSULTATION

CAR-certified MDs
Nurse coordinator
Social worker
Apheresis staff

COLLECTION

Cell therapy/donor room
Laboratory medicine
Nurse coordinator
Manufacturers, FACT

BRIDGING

Non-CAR MDs
CAR MDs
Nursing

INFUSION

CAR MDs
Cell therapy
Nursing
Pharmacy
FACT

LATE CARE

CAR MDs
Non-CAR MDs

REGULATION

Financial services
Billing
Data management
FACT, CIBMTR, FDA

EARLY CARE

CAR MDs
ICU, neurology
Nursing
Pharmacy
FDA

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Cost

Adherence

Respect of patient’s values

Clinical Benefit

Health Literacy

Scheduling

and administration

Social Support

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REFERENCES:

Fesnak, A., June, C. & Levine, B. Engineered T cells: the promise and challenges of cancer immunotherapy. Nat Rev Cancer 16, 566–581 (2016)
Hill JA, Seo SK. How I prevent infections in patients receiving CD19-targeted chimeric antigen receptor T cells for B-cell malignancies. Blood. 2020 Aug 20;136(8):925-935.
Munshi NC, Anderson LD Jr, Shah N, Madduri D, Berdeja J, Lonial S, Raje N, Lin Y, Siegel D, Oriol A, Moreau P, Yakoub-Agha I, Delforge M, Cavo M, Einsele H, Goldschmidt H, Weisel K, Rambaldi A, Reece D, Petrocca F, Massaro M, Connarn JN, Kaiser S, Patel P, Huang L, Campbell TB, Hege K, San-Miguel J. Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma. N Engl J Med. 2021 Feb 25;384(8):705-716.
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Buitrago J, Adkins S, Hawkins M, Iyamu K, Oort T. Adult Survivorship: Considerations Following CAR T-Cell Therapy. Clin J Oncol Nurs. 2019;23(2):42-48. doi:10.1188/19.CJON.S1.42-48
Van Oekelen, O., Aleman, A., Upadhyaya, B. et al. Neurocognitive and hypokinetic movement disorder with features of parkinsonism after BCMA-targeting CAR-T cell therapy. Nat Med 27, 2099–2103 (2021). https://doi.org/10.1038/s41591-021-01564-7

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REFERENCES:

Schuster SJ, Bishop MR, Tam CS, Waller EK, Borchmann P, McGuirk JP, Jäger U, Jaglowski S, Andreadis C, Westin JR, Fleury I, Bachanova V, Foley SR, Ho PJ, Mielke S, Magenau JM, Holte H, Pantano S, Pacaud LB, Awasthi R, Chu J, Anak Ö, Salles G, Maziarz RT; JULIET Investigators. Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma. N Engl J Med. 2019 Jan 3;380(1):45-56.
Wang M, Munoz J, Goy A, Locke FL, Jacobson CA, Hill BT, Timmerman JM, Holmes H, Jaglowski S, Flinn IW, McSweeney PA, Miklos DB, Pagel JM, Kersten MJ, Milpied N, Fung H, Topp MS, Houot R, Beitinjaneh A, Peng W, Zheng L, Rossi JM, Jain RK, Rao AV, Reagan PM. KTE-X19 CAR T-Cell Therapy in Relapsed or Refractory Mantle-Cell Lymphoma. N Engl J Med. 2020 Apr 2;382(14):1331-1342.
Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, Bader P, Verneris MR, Stefanski HE, Myers GD, Qayed M, De Moerloose B, Hiramatsu H, Schlis K, Davis KL, Martin PL, Nemecek ER, Yanik GA, Peters C, Baruchel A, Boissel N, Mechinaud F, Balduzzi A, Krueger J, June CH, Levine BL, Wood P, Taran T, Leung M, Mueller KT, Zhang Y, Sen K, Lebwohl D, Pulsipher MA, Grupp SA. Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. N Engl J Med. 2018 Feb 1;378(5):439-448.
Lee SJ, McQueen RB, Beinfeld M, Fluetsch N, Whittington MD, Pearson SD, Ollendorf DA. Anti B-Cell Maturation Antigen CAR T-cell and Antibody Drug Conjugate Therapy for Heavily Pre-Treated Relapsed and Refractory Multiple Myeloma; Evidence Report. Institute for Clinical and Economic Review, April 5, 2021
Lee DW, Santomasso BD, Locke FL, Ghobadi A, Turtle CJ, Brudno JN, Maus MV, Park JH, Mead E, Pavletic S, Go WY, Eldjerou L, Gardner RA, Frey N, Curran KJ, Peggs K, Pasquini M, DiPersio JF, van den Brink MRM, Komanduri KV, Grupp SA, Neelapu SS. ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. Biol Blood Marrow Transplant. 2019 Apr;25(4):625-638. doi: 10.1016/j.bbmt.2018.12.758. Epub 2018 Dec 25. PMID: 30592986.

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REFERENCES:

Buechner J, Grupp SA, Hiramatsu H, Teachey DT, Rives S, Laetsch TW, Yanik GA, Wood P, Awasthi R, Yi L, Chassot-Agostinho A, Eldjerou LK, De Moerloose B. Practical guidelines for monitoring and management of coagulopathy following tisagenlecleucel CAR T-cell therapy. Blood Adv. 2021 Jan 26;5(2):593-601.
Hay KA, Hanafi LA, Li D, Gust J, Liles WC, Wurfel MM, López JA, Chen J, Chung D, Harju-Baker S, Cherian S, Chen X, Riddell SR, Maloney DG, Turtle CJ. Kinetics and biomarkers of severe cytokine release syndrome after CD19 chimeric antigen receptor-modified T-cell therapy. Blood. 2017 Nov 23;130(21):2295-2306.
Cohen MZ, Jenkins D, Holston EC, Carlson ED. Understanding health literacy in patients receiving hematopoietic stem cell transplantation. Oncol Nurs Forum. 2013 Sep;40(5):508-15.
Evans, K. R., Lewis, M. J., & Hudson, S. V. (2011). The Role of Health Literacy on African American and Hispanic/Latino Perspectives on Cancer Clinical Trials. Journal of Cancer Education, 27(2), 299–305.